OA21041A - Peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory diseases. - Google Patents

Abstract

The present invention provides novel peptide inhibitors of the interleukin-23 receptor, and related compositions and methods of using these peptide inhibitors to treat or prevent a variety of diseases and disorders, including inflammatory bowel diseases.<img file="OA21041A_A0001.tif"/>

Description

PEPTIDE INHIBITORS OF INTERLEUKIN-23 RECEPTOR AND THEIR USE TO TREAT

INFLAMMATORY DISEASES

CROSS REFERENCES TO RELATED APPLICATIONS

[0001] This applications daims priorîty to U.S. Provisional Application No. 62/961,624, filed January 15, 2020, which is incorporated herein in its entirety for ail purposes.

SEQUENCE LISTING

[0002] This application is being filed electronicaily via EFS-Web and includes an électron îcall y submitted sequence listing in .txt format. The .txt file contains a sequence listing entitled “056365_516001 WO_Sequence_Listing_ST25.txt” created on January 11, 2021 and having a size of about 336 kilobytes. The sequence listing contained in this .txt file is part of the spécification and îs incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0003] The present invention relates to novel peptide înhibitors of the interleukin-23 receptor (IL23R), and their use to treat or prevent a variety of diseases and disorders, including inflammatory bowel disease, Crohn’s disease, ulcerative colitis and psoriasis.

BACKGROUND

[0004] The interleukin-23 (IL-23) cytokine has been implicated as playing a crucial rôle in the pathogenesis of autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel diseases (IBDs), e.g., ulcerative colitis and Crohn’s disease. Studies in acute and chronic mouse models of IBD revealed a primary rôle of IL-23R and downstream eHector cytokines in disease pathogenesis. IL-23R is expressed on various adaptive and innate immune cells including Thl7 cells, γδ T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphoid cells, which are found abundantly in the intestine. At the intestine mucosal surface, the gene expression and protein levels of IL-23R are found to be elevated in IBD patients. It is believed that IL-23 médiates this effect by promoting the development of a pathogenic CD4⁺ T cell population that produces IL-6, IL-17, and tumor necrosis factor (TNF).

100051 Production of IL-23 is enriched in the intestine, where ît is believed to play a key rôle in regulating the balance between tolérance and immunity through T-cell-dependent and T-cellindependent pathways of intestinal inflammation through effects on T-helper 1 (Thl) and fh 17assocîated cytokines, as well as restraining regulatory T-cell responses in the gut, favoring inflammation. In addition, polymorphisms in the IL-23 receptor (IL-23R) hâve been associated with susceptibility to inflammatory bowel diseases (IBDs), further estabiishing the critical rôle of the IL-23 pathway in intestinal homeostasîs.

10006] Psoriasis, a chronic skin disease affecting about 2%-3% of the general population has been shown to be mediated by the body’s T cell inflammatory response mechanisms. 11-23 has one of several interleukins împlicated as a key player in the pathogenesis of psoriasis, purportedly by maintaining chronic autoimmune inflammation via the induction of interleukin-17, régulation of T memory cells, and activation of macrophages. Expression of IL-23 and IL-23R has been shown to be increased in tissues of patients with psoriasis, and antibodies that neutralize IL-23 showed IL-23-dependent inhibition of psoriasis development in animal models of psoriasis.

100071 IL-23 is a heterodimer composed of a unique pl 9 subunit and the p40 subunit shared with IL-I2, which is a cytokine involved în the development of interferon-γ (IFN-y)-producing T helper 1 (ThI) cells. Although IL-23 and IL-12 both contain the p40 subunit, they hâve different phenotypic properties. For example, animais déficient in IL-12 are susceptible to inflammatory autoimmune diseases, whereas IL-23 déficient animais are résistant, presumably due to a reduced number of CD4⁺ T cells producing IL-6, IL-17, and TNF in the CNS of IL-23-deficient animais. IL-23 binds to IL-23R, which is a heterodimeric receptor composed of IL-12Κβ1 and 1L-23R subunits. Binding of IL-23 to IL-23R activâtes the Jak-stat signaling molécules, Jak2, Tyk2, and Statl, Stat 3, Stat 4, and Stat 5, although Stat4 activation is substantially weaker and different DNA-binding Stat complexes form in response to IL-23 as compared with IL-12. IL-23R associâtes constitutively with Jak2 and in a ligand-dépendent manner with Stat3. In contrast to IL12, which acts mainly on naive CD4(+) T cells, IL-23 preferentieliy acts on memory CD4(+) T cells.

[0008] Efforts hâve been made to îdentify therapeutic moieties that inhibit the IL-23 pathway, for use in treating IL-23-related diseases and dîsorders. A number of antibodies that bind to IL-23 or IL-23R hâve been identified, including ustekinumab, an antibody that binds the p40 subunît of IL23, which has been approved for the treatment of moderate to severe placque psoriasis, active psoriatic arthritis, moderately to severely active Crohn’s disease and moderately to severly active ulcerative coiitis. More recently, polypeptide inhîbitors that bind to IL-23R and inhibit the binding of IL-23 to IL-23R hâve been identified (see, e.g., US Patent Application Publication No.

US2013/0029907). Clinical trials in Crohn’s Disease or psoriasis with briakinumab (which also target the common p40 subunit) and tildrakîzumab, guselkumab, MEDI2070, and BI-655066 (which target the unique p 19 subunit of IL-23) highlight the potential of ÏL-23 sîgnaling blockade in treatment of human inflammatory diseases. While these findings are promising, challenges remain with respect to identifying stable and sélective agents that preferentially target the IL-23 pathway in the intestine, which can be used for the treatment of intestinal inflammation, such as intestinal bowel diseases, including Crohn’s disease, ulcerative colitis and related disorders.

[0009] Clearly, there remains a need in the art for new therapeutics targetîng the IL-23 pathway, which may be used to treat and prevent lL-23-asociated diseases, including those associated with autoimmune inflammation in the intestinal tract. In addition, compounds and methods for spécifie targeting of IL-23R from the luminal side of the gut may provide therapeutîc benefit to IBD patients sufferîng from local inflammation of the intestinal tissue. The présent invention addresses these needs by providing novel peptide inhibitors that bind IL-23R to inhibit IL-23 binding and sîgnaling and which are suitable for oral administration.

BRIEF SUMMARY OF THE INVENTION

[0010] The présent invention provides inter alia novel peptide inhibitors of IL-23R and related methods of use.

[0011] In a first aspect, the présent invention provides a peptide inhibitor of an interleukin-23 receptor, or a pharmaceutically acceptable sait or solvaté thereof, wherein the peptide inhibitor comprises or consists of an amino acid sequence of Formula (I):

X3-X4-X5-X6-X7-X8-X9-XIO-X11-X12-XI3-X14-X15-XI6 (I) wherein

X3 îs absent or any amino acid;

X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide);

X5 is Cit, Glu, Gly, substituted Gly, Leu, Ile, beta-Ala, Ala, Lys, Asn, Pro, Ser, alpha-MeGIn, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gin, or Asp;

X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGIn, alpha-MeLys, alpha-MeLeu, alphaMeAsn, alpha-MeThr, alpha-MeSer, or Val;

X7 is unsubstituted Trp, or Trp substituted with cyano, halo, alkyi, haloaîkyl, hydroxy, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

h ⁴

X8 is Gin, alpha-MeLys, aipha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, substituted Phe, Tyr, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, Lys(b-Ala), Lys(Gly), Lys(Benzyl, Ac), Lys(butyl, Ac), Lys(isobutyl,Ac), Lys(propyl,Ac), or Trp;

X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Peu, or Pen(sulfoxide);

X ] 0 is Tyr, or substituted Tyr, unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamîdo, 2-aminoethoxy, or 2acetylaminoethoxy; and

XL 1 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy;

X12 is 4-amino-4~carboxy-tetrahydropyran (THP), Acvc, alpha-MeLys, aipha-MeLeu, alphaMeArg, alpha-MePhe, aipha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, cyclohexyiAla, Lys, or Aib;

X13 is any amino acid;

X14 is any amino acid;

and

i) X 15 is any amino acid other than His, (D)His, substituted or unsubstituted His, 2Pal, 3Pal, or 4Pal; X16 is Sarc, aMeLeu, (D)NMeTyr, His, (D)Thr, bAla, Pro, or (D)Pro; and the peptide inhibitor is other than

Ac-[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal|-[THP]-[Lys(Ac)]-NNPG-NH₂;

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu][Lys(Ac)]-NN-[Sarc]-NH₂;

Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal][a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂; or

Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[Aib]-[bA]-NH₂;

or ii) X15 is His, (D)His, substituted or unsubstituted His, 2Pal, 3Pal, 4Pal, 4TriazolAla, or 5Pyal; and X16 is absent, (D)aMeTyr, (D)NMeTyr or any amino acid other than THP, substituted or unsubstituted Phe, substituted or unsubstituted (D)Phe, substituted or unsubstituted His, substituted or unsubstituted (D)His, substituted or unsubstituted Trp, substituted or unsubstituted 2-Nal, or N-substituted Asp; and the compound is other than

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-NH₂;

wherein 2Pa! is 2-pyridyl substituted alanine, and 3Pal is 3-pyridyl substituted alanine, and 4Pal îs 4-pyridyl substituted alanine

5Pyal is 5-pyrîmidine substituted alanine:

O

and wherein X4 and X9 form a disulfide bond, or a thioether bond;

and wherein the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor.

[0012] In certain embodiments, X15 is any amino acid other than His, (D)His, or substituted or unsubstituted His, 2Pal, 3Pal, or 4Pal; XI6 is Sarc, aMeLeu, (D)NMeTyr, His, (D)Thr, bAla, Pro, or (D)Pro; and the peptide inhibitor is other than;

Ac-[Abu]-QTWQC]-[Phe[4-(2-aminoetlioxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NNPG-NH₂;

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu][Lys(Ac)]-N'N-[Sarc]-NH₂;

Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal][a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂; or

Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[Aîb]-[bA]-NH₂.

[0013] In certain embodiments, X15 is His, (D)His, or substituted or unsubstituted His, 2Pal, 3Pal, 4Pal, or 5Pyal; and X16 is absent, (D)aMeTyr, (D)NMeTyr or any amino acid other than THP, substituted or unsubstituted Phe, substituted or unsubstituted (D)Phe, substituted or unsubstituted His, substituted or unsubstituted (D)His, substituted or unsubstituted Trp, substituted or unsubstituted 2-Nai, or N-substituted Asp.

[00141 In certain embodiments, XI5 is 2Pal, 3Pal, or 4Pal; and X16 is Sarc, aMeLeu, (D)Thr, bAla, Pro, or (D)Pro. In certain embodiments, X15 is 2Pal, 3Pal, or 4Pal; and X16 is Sarc. In certain embodiments, X15 is 2Pal, 3Pal, or 4Pal; and XI6 is absent.

[0015] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of

Formula (la), (Ib), (le), or (Id):

X3-X4-X5-X6-X7-X8-X9-X10-X11 -XI2-X13-X14-X15-Sarc (la),

X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X 15-(D)NMeTyr (Ib), X3-X4-X5-X6-X7-X8-X9-XI0-X1 l-X12-X13-X14-[Pal]-X16 (le) X3-X4-X5-X6-X7-X8-X9-X10-X1 l-X12-X13-X14-[His’]-X16 (Id) wherein Pal is 2Pal, 3Pal, or 4Pal; XI6 is absent;

wherein 2Pal is 2-pyridyl substituted alanine, and 3Pal is 3-pyridy 1 substituted alanine, and 4Pal is 4-pyrîdyl substituted alanine

His’ is His or 3-MeHis; X16 is absent; and X4 and X9 form a disulfide bond or a thioether bond; and wherein X4 and X9 form a disulfide bond or a thioether bond.

[0016[ In certain embodiments, the peptide inhibitor comprises an amino acid sequence of Formula (la):

X3-X4-X5-X6-X7-X8-X9-X10-XI l-X 12-X 13-X 14-X 15-Sarc (la) wherein X4 and X9 form a disulfide bond or a thioether bond.

[0017] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of Formula (Ib)

X3-X4-X5-X6-X7-X8-X9-X10-X 1 i -X12-X 13-X 14-X 15-(D)NMeTyr (Ib) wherein X4 and X9 form a disulfide bond or a thioether bond.

[0018] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of Formula (le):

X3-X4-X5-X6-X7-X8-X9-X10-X1 l-X12-X13-XI4-[Pal]-X16 (le) wherein Pal is 2Pal, 3PaI, or 4Pal; X16 is absent;

wherein 2Pal is 2-pyridyl substituted alanine, and 3Pal is 3-pyridyI substituted alanine, and 4Pal is 4-pyridyl substituted alanine

and X4 and X9 form a disulfîde bond or a thioether bond.

[0019] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of

Formula (Id):

X3-X4-X5-X6-X7-X8-X9-X10-X11 -XI2-X13-X14-[His’]-X 16 (Id) wherein His’ is His or 3-MeHis; X16 is absent; and X4 and X9 form a disulfîde bond or a thioether bond.

[0020] In certain embodiments, the monocyclic peptide is a peptide where the peptide îs cyclized via a Pen-Pen disulfîde bond, or via Abu-Cys or Abu-Pen thioether bond.

[0021[ In certain embodiments, X5 is Cit, Glu, Gly, Leu, Ile, beta-Ala, Ala, Lys, Asn, Pro, alphaMeGIn, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gin, or Asp.

[0022] In certain embodiments, X6 is Thr, Aîb, Asp, Dab, Gly, Pro, Ser, alpha-MeGIn, alphaMeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val.

[0023| In certain embodiments, X6 is (D)Asp, (D)Dap, or (D)Lys.

[0024] In certain embodiments, X8 is Gin, alpha-MeLys, alpha-MeLeu, alpha-MeLys(Ac), betahomoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGIn, alpha-MeAsn, Lys(Ac), Dab(Ac), 20 Dap(Ac), homo-Lys(Ac), l-Nal, 2-Nal, or Trp. In certain embodiments, X8 is Lys(Gly) or Lys(bAla).

[0025] In certain embodiments, XI2 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alphaMeTyr, Ala, or cyclohexylAla, Lys, or Aib.

[0026] In a particular embodiment, X15 îs any amino acid, and X16 is Sarc, aMeLeu, (D)Thr, bAla, Pro, or (D)Pro.

[0027] In a more particular embodiment, X15 îs any amino acid, and X16 is Sarc.

[0028] In a second aspect, the présent invention provides a peptide inhibitor of an interleukîn-23 receptor, or a pharmaceutically acceptable sait or solvaté thereof, wherein the peptide inhibitor 30 comprises or consîsts of an amino acid sequence of Formula (Ilia), (Illb), (IIIc), or (Illd):

⁸

Pen- Asn-X6-X7-X8-Pen-X10-Xl l-X12-X13-X14-[Pal]-X16 (Ilia), Pen-Gln-X6-X7-X8-Pen-X10-X 11-X12-X13-X l4-[Pal]-X16 (Illb), Abu- Asn-X6-X7-X8-Cys-X10-XI l-X12-X13-X14-[Pal]-Xl 6 (IIIc), or Abu-Gln-X6-X7-X8-Pen-X10-Xl 1-X12-XI 3-X14-[Pal]-X16 (Illd), wherein X6-X8 and XI0-X14 are as described for Formula (I); Pal is 2Pal, 3Pal, or 4Pal; and X16 is any amino acid; and the peptide inhibitor is cyciized via a Pen-Pen disulfide bond; or a AbuCys or Abu-Pen thîoether bond; and wherein the peptide inhibitor inhîbîts the binding of an interleukin-23 (IL-23) to an fL-23 receptor.

[0029] In another aspect, the présent invention provides a peptide inhibitor of an interleukin-23 10 receptor, or a pharmaceutically acceptable sait or solvaté thereof, wherein the peptide inhibitor comprises or consists of an amino acid sequence of Fonnula ((IVa), (IVb), (IVc), or (IVd):

Pen- Asn-X6-X7-X8-Pen-X10-Xl 1-X12-X13-X14-X15-Sarc (IVa), Pen-Gln-X6-X7-X8-Pen-X10-Xl 1-X12-X13-X14-Xl5-Sarc (IVb), Abu- Asn-X6-X7-X8-Cys-X10-Xl l-X12-XI3-X14-X15-Sarc (IVc), or

Abu-Gln-X6-X7-X8-Pen-Xl 0-X1 l-XÎ2-X13-X14-X15-Sarc (IVd), wherein X6-X8 and XI0-XI4 are as described for Formula (I); X15 is any amino acid; and the peptide inhibitor is cyciized via a Pen-Pen disulfide bond; or a Abu-Cys or Abu-Pen thîoether bond; and wherein the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL23 receptor.

[0030] In certain embodiments, X5 is Cit, Glu, Gly, Lys, Asn, Ser, Pro, alpha-MeGln, alphaMeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homoLys(Ac), Gin, or Asp. In certain embodiments, X5 is Cit, Glu, Gly, Leu, Ile, beta-Ala, Ala, Lys, Asn, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alphaMeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gin, or Asp.

[0031] In certain embodiments, X8 is Gin, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), betahomoGln, Cit, Glu, Phe, Asn, Thr, Val, Aîb, alpha-MeGln, alpha-MeAsn, Lys(Ac), alphaMeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, or Trp. In certain embodiments, X8 is Gin, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGIn, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, 30 or Trp. In certain embodiments, X8 is Lys(Gly) or Lys(bAla).

[0032] In certain embodiments, X8 is Gin, alpha-Me-Lys, alpha-MeLeu, alpha-MeLys(Ac), betahomoGIn, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, Trp, or Lys(R’); and wherein R’ is Aib, bAla, IVA, Ala, cyclohexanoic, octanoic, -C(O)CH₂Ph (-C(O)benzyl), trifluorpropionic, Gly, acetyl, valeric, or trifluoroacetyl; and R’ is attached to Ν^ε of Lys. In certain embodiments, X8 is Asn, alpha-Me-Lys, alpha-MeLeu, Aib, Cit, or Lys(R’). In certain embodiments, X8 is Lys(R’). In certain embodiments, R’ is acetyl. In another embodiment R’ is Gly, Aib, Ala, or bAla. In certain embodiments, R’ is Gly, or Aib.

[0033] In certain embodiments, X8 is Lys(Gly) or Lys(bAla).

[0034] in certain embodiments, X4 is Abu and X9 is Cys, (D)Cys, alpha-MeCys, (D)Pen, or Pen. In certain embodiments, X4 is Cys, (D)Cys, alpha-MeCys, (D)Pen, or Pen; and X9 is Abu. In certain embodiments, each X4 and X9 is independently Cys, (D)Cys, aipha-MeCys, (D)Pen, or Pen. In certain embodiments, each X4 and X9 is Cys, (D)Cys, alpha-MeCys, (D)Pen, or Pen.

[0035] In one particular embodiment, X3 is absent.

[0036] In another particular aspect, the présent invention provides a peptide inhibitor of an interleukin-23 receptor, or a pharmaceutically acceptable sait or solvaté thereof, wherein the peptide inhibitor comprises or consists of an amino acid sequence of Formula (Z):

R'-X-R² (Z) or a pharmaceutically acceptable sait or solvaté thereof, wherein

R¹ is a bond, hydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12 aryl C1-C6 alkyl, a C1-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing; X is the amino acid sequence of Formula (I),(Ia), (Ib), (le), (Id), (Il)-(XVIIId), or an amino acid sequence set forth in Table El A, and R² is OH or NIL.

[0037] In certain embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of Formula (Z):

RLX3-X4-X5-X6-X7-X8-X9-X10-X11 -XI2-X13-X14-X15-X16-R² (Z’) or a pharmaceutically acceptable sait thereof, wherein

R¹ is a hydrogen, Ac, a C1-C6 alkyl, a C6-C12 aryl, a C6-CI2aryl-Cl-6alkyl, a C1-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing; and R² is OH or NH₂.

[0038] In particular embodiments of any of the peptide inhibitors disclosed herein, including peptide inhibitors comprising an amino acid sequence of Formula Formula (li)-(XVIIld), X4 is Pen and X9 is Pen, and the bond is a disulfide bond.

[0039] In particular embodiments, any of the peptide inhibitors described herein comprise one or more half-life extension moiety and/or one or more linker moiety conjugated to the peptide . 10 inhibitor. In particular embodiments, the half-life extension moiety is conjugated to the peptide inhibitor via one or more linker inoieties.

[0040] In certain embodiments, any of the peptide inhibitors described herein further comprises a conjugated Chemical substituent. In particular embodiments, the conjugated Chemical substituent is a lipophilie substituent or a polymeric moiety, e.g., Ac, Palm, gamaGlu-Palm, îsoGlu-Palm, PEG2-Ac, PEG4-isoGlu-Palm, (PEG)₅-Palm, succinic acid, giutaric acid, pyroglutaric acid, benzoic acid, IVA, octanoic acid, 1,4 diaminobutane, isobutyl, Alexa488, A!exa647, or biotin. In certain embodiments, the conjugated Chemical substituent is a polyethylene glycol with a molecular mass of 400 Da to 40,000 Da. In particular embodiments, the peptide is conjugated at

X8. In another particular embodiment, the peptide is conjugated at X9. In a more particular embodiment, the peptide is conjugated at X] 0.

[0041] In a related aspect, the present invention includes a peptide dîmer inhibitor of an interleukin-23 receptor, wherein the peptide dimer inhibitor comprises two peptide monomer subunits connected via one or more linker moietîes, wherein each peptide monomer subunit comprises a sequence of Formula (I),(Ia), (Ib), (le), (ld), (Il)-(XVIIId), or any other sequence or structure set forth herein. In certain embodiments, one or both peptide monomer subunit îs cyclized via an intramolecular bond between X4 and X9. In certain embodiments, one or both intramolecular bond is a disulfide bond or a thioether bond. In certain embodiments, the linker îs any of those shown in Table 2 or described herein. In certain embodiments, the linker moiety is a dîethylene glycol linker, an iminodiacetic acid (IDA) linker, a β-Ala-iminodiaceticacid (β-AlaIDA) linker, or a PEG linker. In particular embodiments, the N-terminus of each peptide monomer subunit is connected by the linker moiety. In particular embodiments, the C-termînus of each peptide monomer subunit îs connected by the linker moiety. In certain embodiments, the linker connects an internai amino acid residue of at least one of the peptide monomer subunits to the N- terminus, C-terminus, or an internai amino acid residue of the other peptide monomer subunit.

[0042] In a further related aspect, the present invention includes a polynucleotide comprising a sequence encoding a peptide inhibitor of the present invention or one or both peptide monomer subunit of a peptide dimer inhibitor of the present invention. The present invention also includes a vector comprising the polynucleotide.

[0043] In another aspect, the present invention includes a pharmaceutical composition comprising a peptide inhibitor or a peptide dimer inhibitor of the present invention, and a pharmaceutically acceptable carrier, excipient, or diluent. In particular embodiments, the pharmaceutical k ¹¹ composition comprises an enteric coating. In certain embodiments, the enteric coating protects and releases the pharmaceutical composition within a subject’s Iower gastrointestinal System.

[0044] In another aspect, the présent invention includes a method for treating or preventing a disease associated with IL-23 signalling, including but not limited to an Inflammatory Bowel

Disease (IBD), ulcerative colitis, Crohn’s disease, Celiac disease (nontropical Sprue), enteropathy associated with séronégative arthropathîes, microscopie colitis, collagenous colitis, éosinophilie gastroenteritis, colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency-1, chronic granulomatous disease, glycogen storage disease type 1 b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-

Aldrich Syndrome, pouchitis resulting after proctocolectomy and ileoanal anastomosîs, gastro intestinal cancer, pancreatitîs, insu lin-dépendent diabètes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, or graft versus host disease in a subject, comprising providing to the subject an effective amount of a peptide inhibitor or pharmaceutical composition of the présent invention. In certain embodiments, the inflammatory bowel disease is ulcerative colitis or Crohn’s disease. In particular embodimnts, the peptide inhibitor or the peptide dimer inhibitor inhibits bindîng of an interleukin-23 (IL-23) to the interleukîn-23 receptor (IL-23R). In certain embodiments, the pharmaceutical composition is provided to the subject by an oral, intravenous, peritoneal, intradermal, subeutaneous, intramuscular, intrathecal, inhalation, vaporization, nebulization, sublingual, buccal, parentéral, rectal, intraocular, inhalation, vaginal, or topical route of administration. In particular embodiments, the pharmaceutical composition is provided orally for treating Inflammatory Bowel Disease (IBD), ulcerative colitis, Crohn’s disease. In certain embodiments, the pharmaceutical composition is provided to the subject topically, parenterally, intravenously, subcutaneously, peritonealy, or intravenously for treating psoriasis.

DETAILED DESCRIPTION OF THE INVENTION

DEFINITIONS

[0045] Unless otherwise defined herein, scientific and technical ternis used in this application shall hâve the meanings that are commonly understood by those of ordinary skill in the art.

Generally, nomenclature used in connection with, and techniques of, chemistry, molecular biology, cell and cancer bioiogy, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry, described herein, are those well-known and commonly used in the art.

[00461 As used herein, the following ternis hâve the meanings ascribed to them unless specified otherwise.

[0047] Throughout this spécification, the word “comprise” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer (or components) or group of integers (or components), but not the exclusion of any other integer (or components) or group of integers (or components).

[0048[ The singular forms “a,” “an,” and “the” include the plurals unless the context clearly dictâtes otherwise.

[0049] The terni “including” is used to mean “including but not limited to.” “Including” and “including but not limited to” are used interchangeably.

[0050] The ternis “patient,” “subject,” and “individual” may be used interchangeably and refer to either a human or a non-human animal. These terms include mammals such as humans, primates, livestock animais (e.g., bovines, porcines), companion animais (e.g., canines, felines) and rodents (e.g., mice and rats).

[0051] The terni “peptide,” as used herein, refers broadly to a sequence of two or more amino acids joined together by peptide bonds. It should be understood that this terni does not connote a spécifie length of a polymer of amino acids, nor is it intended to imply or distinguish whether the polypeptide is produced using recombinant techniques, Chemical or enzymatîc synthesis, or îs naturally occurring. The term peptide include cyclic peptides.

[00521 The recitations “sequence identity”, “percent identity”, “percent homology”, or, for example, comprising a “sequence 50% identical to,” as used herein, refer to the extent that sequences are identical on a nucleotide-by-nucleotide basis or an amino acid-by-amino acid basis over a wîndow of comparison. Thus, a “percentage of sequence identity” may be calculated by comparing two optimally aligned sequences over the window of comparison, detennîning the number of positions at which the identical nucleic acid base (e.g.. A, T, C, G, I) or the identical amino acid residue (e.g., Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gin, Cys and Met) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e., the window size), and multiplying the resuit by 100 to yield the percentage of sequence identity.

[0053] Calculations of sequence similarity or sequence identity between sequences (the terms are used interchangeably herein) can be performed as follows. To détermine the percent identity of two amino acid sequences, or of two nucleic acid sequences, the sequences can be aligned for h ¹³ optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In certain embodiments, the length of a reference sequence alîgned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 5 50%, 60%, and even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence. The amino acid residues or nucléotides at corresponding amino acid positions or nucieotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucieotide as the corresponding position in the second sequence, then the molécules are îdentical at that position.

[0054] The percent identity between the two sequences is a fonction of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

[0055] The comparison of sequences and détermination of percent identity between two sequences can be accomplished using a mathematical algorithm. In some embodiments, the percent identity 15 between two amino acid sequences is determined using the Needleman and Wunsch, (1970, J.

Mol. Biol. 48: 444-453) algorithm which has been incorporated into the GAP program in the GCG software package, using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1,2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucieotide sequences is determined using the GAP program in 20 the GCG software package, using an NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. Another exemplary set of parameters includes a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5. The percent identity between two amino acid or nucieotide sequences can also be determined using the algorithm ofE. Meyers and W. Miller (1989, Cabios, 4; 11-17) which has 25 been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.

[0056] The peptide sequences described herein can be used as a “query sequence” to perform a search against public databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 30 2.0) of Altschul, et al., (1990, J. Mol. Biol, 215; 403-10). BLAST nucieotide searches can be performed with the NBLAST program, score = 100, wordlength = 12 to obtain nucieotide sequences homologous to nucleic acid molécules of the invention. BLAST protein searches can be performed with the XBLAST program, score = 50, wordlength = 3 to obtain amîno acid sequences homologous to protein molécules of the invention. To obtain gapped alignments for comparison purposes, Oapped BLAST can be utilized as described in Altschul et al. (Nucleic Acids Res. 25:3389-3402, 1997). When utîlizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.

[0057] The term conservative substitution as used herein dénotés that one or more amino acids are replaced by another, biologicaily similar residue. Examples include substitution of amino acid residues with similar characteristîcs, e.g., small amino acids, acidic amino acids, polar amino acids, basic amino acids, hydrophobie amino acids and aromatic amino acids. See, for example, the table below. In some embodiments of the invention, one or more Met residues are substituted with norleucine (Nie) which is a bioisostere for Met, but which, as opposed to Met, is not readily oxidized. Another example of a conservative substitution with a residue normally not found in endogenous, mammalian peptides and proteins is the conservative substitution of Arg or Lys with, for example, ornithine, canavanine, aminoethyl cysteine or another basic amino acid. In some embodiments, one or more cysteines of a peptide analogue of the invention may be substituted with another residue, such as a serine. For further information concerning phenotypically silent substitutions in peptides and proteins, see, for example, Bowie et.al. Science 247, 1306-1310, 1990. In the scheme below, conservative substitutions of amino acids are grouped by physicochemical properties. I: neutral, hydrophilic, II: acids and amides, III: basic, IV: hydrophobie, V: aromatic, bulky amino acids.

I	II	III	IV	V
A	N	H	M	F
S	D	R	L	Y
T	E	K	I	w
P	Q		V
G			c

[Û058] In the scheme below, conservative substitutions of amino acids are grouped by physicochemical properties. VI: neutral or hydrophobie, VII: acidic, VIII; basic, IX: polar, X: aromatic.

•	15
VI	VII	VIII	IX	X
	A	E	H	M	F
	L	D	R	S	Y
	I		K	T	w
	P			c
	G			N
	V			Q

[0059] The term “amino acid” or “any amino acid” as used here refers to any and ail amino acids, including naturally occurring amino acids (e.g., a-amino acids), unnatural amino acids, modified amino acids, and non-natural amino acids. It includes both D- and L-amino acids. Natural amino 5 acids include those found in nature, such as, e.g., the 23 amino acids that combine into peptide chains to form the building-blocks ofa vast array of proteins. These are primarily L stereoisomers, although a few D-amino acids occur in bacterial envelopes and some antibiotics. The 20 “standard,” natural amino acids are listed in the above tables. The “non-standard,” natural amino acids are pyrrolysine (found in methanogenic organisais and other eukaryotes), selenocysteine 10 (présent in many noneukaryotes as well as most eukaryotes), and N-formylmethionine (encoded by the start codon AUG in bacteria, mitochondria and chloroplasts). “Unnatural” or “non-natural” amino acids are non-proteinogenic amino acids (i.e., those not naturally encoded or found in the genetic code) that either occur naturally or are chemically synthesized. Over 140 unnatural amino acids are known and thousands of more combinations are possible. Examples of “unnatural” amino 15 acids include β-amîno acids (β³ and β²), homo-amîno acids, proline and pyruvic acid dérivatives, 3-substituted alanine dérivatives, glycine dérivatives, ring-substituted phenylalanine and tyrosine dérivatives, linear core amino acids, dîamino acids, D-amino acids, alpha-methyl amino acids and N-methyl amino acids. Unnatural or non-natural amino acids also include modified amino acids. “Modified” amino acids include amino acids (e.g., natural amino acids) that hâve been chemically 20 modified to include a group, groups, or Chemical moiety not naturally présent on the amino acid.

According to certain embodiments, a peptide inhibitor comprises an intramolecular bond between two amino acid residues présent in the peptide inhibitor. It is understood that the amino acid residues that form the bond wil! be altered somewhat when bonded to each other as compared to when not bonded to each other. Reference to a particular amino acid is meant to encompass that 25 amino acid in both its unbonded and bonded State. For example, the amino acid residue homoSerine (hSer) or homoSerine(Cl) in its unbonded form may take the form of 2-aminobutyric h ¹⁶ acid (Abu) when participating in an intramolecular bond according to the present invention. The present invention inclues both peptide inhibitors containing cross-links between X4 and X9, as well as the peptide inhibitors that do not contain cross-links between X4 and X9, e.g., before crosslînk formation. As such, the names hSer and Abu are intended to indicate the same amino acids 5 and are used interchangeably.

[0060] For the most part, the names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the naming conventions suggested by the ILJPAC Commission on the Nomenclature of Organic Chemistry and the IUPAC-1UB Commission on Biochemical Nomenclature as set out in “Nomenclature of α-Amino Acids (Recommendations, 1974)” 10 Biochemistry, 14(2), (1975). To the extent that the names and abbreviations of amino acids and aminoacyl residues employed in this spécification and appended claims differ from those suggestions, they will be made clear to the reader. Some abbreviations use fui in describing the invention are defined below in the following Table 1.

Table 1. Abbreviations of Non-Natural Amino Acids and Chemical Moîeties (for amino acid dérivatives, ail L unless stated)

Abbreviation	Définition
(l-Me)His	(1 -Methyl)Histidine
(D)2-Nal	D-2-N aphthy lal an ine
(D)aMePhe	(D)-alpha-Me-Pheny la lanine
(D)aMeTyr	(D)-alpha-Me-Tyrosine
(D)NMeTyr	NMe(D)Tyr or N-Me-(D)Tyrosine
(D)Om	D-Omithine
(D)Phe[3-NH2]	(D)- (3-Amino)phenylalanine
(D)Phe[4-NH2]	(D)-(4-Amino)phenylalanine
(N-(3-Pyz))Asn	N-Py razo 1 -3 -y 1-Asparagi ne
(N-(4-Pyz))Asn	N-Py razo 1-4-yl-A sparagi ne

Abbreviation	Définition
(N-(5-indoyl))Asn	N-indoi-5-yl-Asparagine
(N-(imidazol-2-yl)methyl)Asn	N-(imidazo-2-yl)methyl-Asparagine
(N-(propylamido))Asn	N-CH2CH2CONH2-Asparagine
(N-2-aininophenyl)Asn	N-Ph(2-NH2)-Asparagîne
(N-3-amînophenyl)Asn	N-Ph(3-NH2)-Asparagine
(N-4-aminophenyl)Asn	N-Ph(4-N H2)-Asparag î ne
(N-benzyl)Asn	N-benzyl-Asparagine
(N-Ph)Asn	N-Ph-Asparagine
(N-pip)Asn	N-piperidin-4-yl-Asparagine
(N-Pyr)Asn	N-Pyrrolidin-3-yl-Asparagine
1,2,3,4-tetrahydro-norharman	L-1,2,3,4-tetrahydro-norharman
1-1-Indane	l-Aminoindane-l-carboxylic acid
1-Nal (also referred to as 1-Nap)	L-1 -Naphthy lalan ine
2,5,7-tert butyl Trp	2,5,7-Tris-tert-butyl-L-tryptophan
2-2-Indane	2-Aminoindane-2-carboxylic acid
2-Nal (also referred to as 2-Nap)	L-2-Naphthylalanine
2-Pal or 2Pal	L-2-Pyridylalanine
3-Pal or 3Pal	L-3-Pyridylalanine

Abbrevîation	Définition
4-am ino-4-c arboxy-piperid ine	4-am i no-2	H ί2ν CO -carboxj	SH '-piperidine
4-am ino-4-carboxytetrahydropyran or THP	h 4-amîno-4-ci	i2n cc irboxy-te	2h trahydropyran
4-Pal or 4Pal	L-4-Pyridylalanine
4-Pyridylalanine	4-L-Pyridylalanine
4TriazolAla	O ΗΐΎ NH2 4-triazole-alanine
5-Hydroxy Trp	5-Hydroxy-L-Tryptophan
5Pyal	O nh2 5-pyrimidine-alanine
6-CbloroTrp	6-Chloro-L-Tryptophan
Abu	2-Aminobutyric acid
Ac-	Acetyl
Acbc	1 -aminocyclobutanecarboxylic acid

	19
Abbreviatîon	Définition
Achc or Achx	Η,Ν CO.H l-atninocyclohexanecarboxylic acid
Acpc or Acpx	H^/^bOiH 1 -aminocyclopropylcarboxylic acid
Acvc	l-aminocydopentanecarboxylic acid
AEA	(2-aminoethoxy)acetic acid
AEP	3-(2-amînoethoxy)propanoic acid
Ahx	6-aminohexanoic acid
Aib	2-aminoisobutyric acid
a-MeAsn, alpha-MeAsn	α-Methyl-L-Asparagine
a-MeGIn, alpha-MeGIn	α-Methy 1-L-G lutam ine
aMeGlu or aMeGlu	alpha-methyl Glutamic Acid
aMePhe(4-F)	a-Methyl-(4-Fluoro)phenylalanine
aMePro	alpha-methyl-L-Proline
Azt	L-azetidine-2-carboxyIic acid
Bip	L-4,4’-Biphenylalanine
Cav	L-Cavanine

Abbreviation	Définition
Cha	Cyc lohexy ί-L-alan ine
Cit	L-Citrulline
CONH2	Carboxamide
COOH	Carboxylic Acid
Coumarin	0 OH XX j]
Cpa	Cyclopentyl-L-alanine
Cyclobutyl	L-cyclobutylalanine
cyclohexylAla	(2- or beta-)-cyclohexyl-L-Alanîne
Dab	L-Diaminobutyric acid
DabCOMeor Dab(Ac)	N-Acetyl-L-diaminobutyric acid
Dap	L-Diaminopropionic acid
DapCOMeor Dap(Ac)	N-Acety!-L-Diaminopropionic acid
DiethylGly	nh2 OH
DMT	2,6-DimethylTyrosine
DTT	Dithiothreîtol

Abbreviation	Définition
FPrpTriazoleMe_Acid	“n a O X
Gla	Gamma-Carboxy-L-Glutamic acid
Gly(N-allylmethyl)	N-allyl-L-Glycine
Gly(N-cyclohexylmethyl)	N-Cyclohexylmethyl-L-Glycine
GlyfN-isobutyl)	N-lsobutyl-L-Glycine
hArg	L-homoArginine
hCha	L-homocyclohexylalanine
His_3Bom	0 _ 1 N\ / 1 v ,N NH2 0
His_3Me or 3MeHis	(3-Methyl)Histidine
His_Bzl	u; h2n oh
hLeu	L-homoLeucine

Abbreviatîon	Définition
hLys(Ac) or homo-Lys(Ac),	homo-L-Lysine
Hph	Homophenylaianine
hPhe(3,4-dimethoxy)	3,4-dimethoxy-L-homophenylalanine
hSer	L-homoSerine
Hy	Hydrogen (Free N-terminal)
Hyp	4-Hydroxy-L-Proline
ÎPr or i-Pr	Iso-Propyl
Lys(Ac)	Ν-ε-acetyl-L-Lysine
Lys(Benzyl,Ac)	NE-acetyl-Ne-benzyl-L-Lysine or Lys(N-acetyl-Nbenzyl) 0 0 ^^2
Lys(butyl,Ac)	NE-acetyl-NE-butyl-L-Lysine or Lys(N-acetyl-Nbutyl) Ύ° o nh2
Lys(C02Allyl)	N-(C(O)2-Allyl)-Lysine
Lys(COCFj)	N-e-trifluoroacetyl-L-Lysine
Lys(C0CF3)	N-Tri fi uoroacety 1 -Ly s î ne
Lys(COcPr)	Lys(CO-cyclopropyl)
Lys(COEt)	N-(C(O)-Et)-Lysine
Lys(COiBu)	N-£-[C(O)-î-Bu]-L-Lysine

Abbreviatîon	Définition
Lys(COiPr)	N-(C(O)-i-Pr)-Lysine
Lys(COPent)	Lys(CO-pentyl)
Lys(COPr)	N-(C(O)-n-Pr)-Lysine
Lys(COtBu)	N-s-[C(O)-t-Bu]-L-Ly$ine
Lys(COtBu)	N-(C(O)-t-Bu)-Lysine
Lys(isobutyl,Ac)	N£-acetyl-NE-isobutyl-L-Lysine or Lys(N-acetyl-Nisobutyl) 1 Ύ° nh2
Lys(propyl,Ac)	NE-acetyl-N£-propyl-L-Lysine or Lys(N-acetyl-Npropyi) Ύ° nh2
Lys(R’)	N-£-[R’]-L-Lysine (exemplary R’= Aib, bAla, 1VA, Ala, cyclohexanoic, octanoîc, -CfOJCHîPh, trifluorpropionic, Gly, acetyl, trifluoroacetyl, etc)
N(N2AmAnil)	N-2-aminoanilinyl-L-asparagine (L-asparagine, N-2aminoanilinyl)
N(N3AmAnil)	N-3-amtnoanilinyl-L-asparagine (L-asparagine, N-3aminoanilinyl)
N(N4AmAnil)	N-4-aminoanilînyl-L-asparagine (L-asparagine, N-4aminoanilinyl)

Abbreviation	Définition
N(NAlkyl)	N-Alkyi-L-asparagine (L-asparagine, N-alkyl) (L)H2N-C(H)(CO2H)-CH2-C(O)-NH(Alkyl)
N(NAmbu)	N-4-aminobutyl-L-asparagine (L-asparagine, N-4aminobutyl)
N(NAnil)	N-anilinyl-L-asparagine (L-asparagine, N-anilinyl)
N(NBu)	N-butyl-L-asparagine (L-asparagine, N-butyl)
N(NBzl)	N-benzyl-L-asparagine (L-asparagine, N-benzyl)
N(Nchx)	N-cyclohexyl-L-asparagine (L-asparagine, Ncyclohexyl)
N(Ncpx)	N-cyclopropyl-L-asparagine (L-asparagine, Ncyclopropyl)
N(NEt)	N-ethyl-L-asparagine (L-asparagine, N-ethyl)
N(NÎBu)	N-isobutyi-L-asparagine (L-asparagine, N-isobutyl)
N(NiPr)	N-isopropyl-L-asparagine (L-asparagine, N-îsopropyl)
N(NMe)	N-methyl-L-asparagîne (L-asparagine, N-methyl)
N(Npip)	N-piperidinyl-L-asparagine (L-asparagine, Npiperidinyl)
N(NtBu)	N-tert-butyl-L-asparagine (L-asparagine, N-tert-butyl)

Abbreviation	Définition
N3_Acid	N3-CH2-COOH
Nie or nL	L-Norleucîne
N-MeAla	N-Methyl-L-Alanine
N-MeArg	N-Methyl-L-Argînine
N-MeAsn	N-Methyl-L-Asparagine
N-MeGln	N-Methyl-L-Glutamine
N-MeLys	N-Methyl-Lysine
N-Me-Lys	N-Methyl-L-Lysîne
N-Me-Lys(Ac)	Ν-ε-Acetyl-N-Methyl-L-lysine
N-MeTrp	N-Methy 1-L-T ry ptophan
NMepA or NMebA	N-Methy l-beta-Alanine
Octgly	L-Octylglycine
Om	L-Omithine
OrnCOMe	0 O H nh2 N-Acetyl-L-ornithine
Pen	L-Penicil lamine
Pen(sulfolxide)	L-Penicillamine(sulfoxide)
Phe((3,4-diOMe)	4-(3,4-dimethoxy)phenylalanine
Phe(2,4-Me2)	2,4-dîmethyl-L-phenylalanine
Phe(3s4-Ch)	3,4-dichloro-L-phenylalanine
Phe(3,4-dimethoxy)	3,4-dimethoxy-L-phenylalanine
Phe(3,5-F2)	3,5-difluoro-L-phenylalanine

Abbreviation	Définition
Phe(4_2ae_Boc)	4-(2-(N-t-Boc)-aminoethoxy)phenylaianine
Phe(4-Br)	4-bromo-L-phenylalanîne
Phe(4-CF3)	4-Trifluoromethyl-L-Phenylalanine
Phe(4-CN)	4-cyano-L-phenylalanine
Phe(4-CO2H)	4-Carboxy-L-pheny [alanine
Phe(4-CONH2) or Phe(Cmd)	4-Carbamoyl-L-phenylalanine
Phe(4-F)	4-Fluoro-L-Phenyl a Janine
Phe-(4-Guanidino)	4-Guanidine-L-Phenylalanîne
Phe(4-Me)	4-methy 1 -L-pheny lalan i ne
Phe(4-N3)	4-azidophenylalanine
Phe(4-NH2), paf	4-amino-L-phenylalanine
Phe(4-OAllyl)	O-^ZZyZ-L-Tyrosîne
Phe(4-OBzl)	O-Benzyl-L-tyrosine
Phe(4-OMe)	4-Methoxy-L-phenylalanine
Phe(4-Phenoxy)	4-Phenoxy-L-phenylalanîne
Phe(penta-F)	pentafluoro-L-phenylalanine
Phe(t-Bu)	Z-butyl-L-phenylalanine
Phe[(aMe)-4-(2-aminoethoxy)]	a- Methyl -4-(2-am inoethoxy )pheny lalan ine
Phe[4-(2-(Npropionylamino)ethoxy	0 h ίΓΎΥΛ0” Λ nh2 Y 0 Z 0
Phe[4-(2-acetylaminoethoxy)] or Phe[4-(2-aminoethoxy)Ac]	L-4-[(Ac-NH-CH2CH2-O)]-Ph-CH2-C(H)(NH2)CO2H or 4-(2-acety lam i noethoxy)-L-pheny lalanine

Abbreviation	Définition
Phe [4-(2-aminoethoxy)] or F(4-2ae)	.NH; 0^ 0 nh2 4-(2-amînoethoxy)-L-phenylalanine
Phe[4-aminomethyl]	(4-aminomethyi)Phenyîalanine
Phe_4Ad	0 kJk/kzOH 0
Phe_4ae_BH	Phe[4-(2-(N-(4-hydroxy-3methylphenyl)propionylamino)ethoxy) 0 Η0ΥΊ h AvV^oh 1 nh2 0
Phe_4ae_Ethyl	Phe[4-(2-(N-propionylamino)ethoxy)]0 h ίΓΥΎΧ°Η -y q-- z 0
Phe_NH2_Ac	Phe[4-(2-aceylaminoethoxy)]- 0 h nrA nh2 0
Pro(4,4diF)	4,4-difluoro-L-Prolîne

Abbreviation	Définition
2Quin	(S)-2-amino-3-(quinolin-2-yl)propanoic acid or 2quinolinylalanine
Quin or 3Quin or 3-Quin	O. L hNH: O^^OH (S)-2-amino-3-(quinolin-3-yl)propanoic acid or 3-quinolinylalanine
Sarc or NMeGly	Sarcosine or N-methylglycine
Spiral_Pip	H Nnh2 HO
i-butyl-Ala	3 - ftert-buty A lan i ne-O//
Z-butyl-Gly	tert-butyl-glycine
Trp_4Aza	4-aza-tryptophan
Trp_7Aza	7-aza-tryptophan
Tyr(3-t-Bu)	3-r-butyl-L-tyrosine
Tyr_CHF2	0 F NH2 F 0 v or L-(4-difluoromethoxy)Phenylalanine
W(4-F)	4-fluoro-L-tryptophan

Abbreviation	Définition
W(5-Ca)	(5-Carboxamido)-L-Tryptophan
W(5-CN)	5-cyano-L-tryptophan
W(5-Ph)	5-Phenyl-Tryptophan
W(6-Ph)	6-Phenyl-Tryptophan
W(7-(1-Nal)	7-(naphth -1 -y 1)-T ryptoph an
W(7-(2-FPh))	7-(2-F 1 uoro-pheny l)Try ptophan
W(7-(2-Nal)	7-(naphth-2-y l)-T ry ptophan
W (7-(3,5-t-Bu-Ph))	7-(3,5 -d i -tert-buty 1 pheny 1)-T ryptophan
W(7-(3BiPh))	7-(biphenyl-3-yi)-Tryptophan
W(7-(3-carboxamidophenyl))	7-(3 -carboxamidopheny 1)-T ryptophan
W(7-(3-CF3Ph))	7-(3-trifluoromethylphenyl)-Tryptophan
W(7-(3-iPrPh))	7-(3-isopropy)phenyl)-T ryptophan
W(7-(3-MePh))	7-(3-methyïphenyl)-T ryptophan
W(7-(3-OCF3Ph))	7-(3-trifluoromethoxyphenyl)-Tryptophan
W(7-(3-OMePh))	7-(3-MethoxyPhenyl)-Tryptophan
W(7-(3-pyrazol-1 -y[))	7-(3-pyrazol-1 -yi)-Tryptophan
W (7-(4-A nthracen- 5-y 1))	7-(4-Anthracen -5 -y 1 )T ryptophan
W(7-(4BiPh))	7-(biphenyl-4-yl)-Try ptophan
W(7-(4-CONH2Ph))	7-(4-carboxam idopheny 1)-Tryptophan
W(7-(4Quin))	7-(quinoline-4-y 1)-T ryptophan
W(7-(Phenanthren-5-yl))	7-(Phenanthren-5 -y l)Try ptophan

Abbreviation	Définition
W(7-CN)	7-cyano-L-tryptophan
W(7-imidazopyridinyi)	7-(imidazopyridinyl)-Tîyptophan
W(7-indazol-5-yl)	7-(indazol-5-yl)-Tryptophan
W(7-Ph)	7-Pheny 1 -T ry ptophan
W(7-pyrimidin-5-yl)	7-(py rimidi n-5 -y l)-T ryptophan
W(7-thienyl)	7-th ieny 1-T ryptophan
β-Ala or bA	Ε-β-Alanine
β-Glu	lY-Glutamic acid
βΗΟΙη or b-hGln, or bhomoGln	L-f-homoglutamine
βΗΟΙυ	L-β-hoπlOglutamic acid
βhPhe	LYhomophenylalanine
βΗΡΓΟ	L-p-homoproline
PhTrp	L-p-homoTryptophan
ot-MeArg, a-MeArg, or alphaMeArg	alpha-methyl-L-Arginine
α-MeCys, alpha-MeCys, or aMeCys	alpha-methyl-L-Cysteine
α-MeLeu, a-MeLeu, alphaMeLeu	alpha-methyl-L-Leucine
a-MeLys(Ac), a-MeLys(Ac), or alpha-MeLys(Ac)	ε-acetyl-aipha-methyl-L-Lysine
α-MeLys, a-MeLys, or alphaMeLys	alpha-methyl-L-Lysine
a-MeOrn	alpha-methyl-L-Omithine

Abbreviation	Définition
oi-MePhe or a-MePhe or a-MePhe	a!pha-methyl-L-Phenylalanine
a-MeTrp	alpha-methyl-L-Tryptophan
oc-MeTyr	alpha-methyl-L-Tyrosine
a-DiethylGly	a-DiethylGlycine
pAla, beta-Ala, or bA	beta-Alanine
phAla	beta homo-L-Alanine
phLeu	beta homo-L-Leucîne
phTrp	beta homo-L-Trptophan
PhTyr	beta homo-L-Tyrosîne
phVal	beta homo-L-Valine

[0061] Throughout the présent spécification, unless naturally occurrîng amino acids are referred to by their full name (e.g., alanine, arginine, etc.), they are designated by their conventional threeletter or single-letter abbreviations (e.g., Ala or A for alanine, Arg or R for arginine, etc.). Unless 5 otherwise indicated, three-letter and single-letter abbreviations of amino acids refer to the Lisomeric form of the amino acid in question. The term “L-amino acid,” as used herein, refers to the “L” isomeric form of a peptide, and conversely the term “D-amino acid” refers to the “D” isomeric form of a peptide (e.g., Dasp, (D)Asp or D-Asp; Dphe, (D)Phe or D-Phe). Amino acid residues in the D isomeric form can be substituted for any L-amino acid residue, as long as the ] 0 desired function is retained by the peptide. D-amino acids may be indicated as customary in lower case when referred to using single-letter abbreviations.

[0062] In the case of less common or non-naturally occurrîng amino acids, unless they are referred to by their full name (e.g. sarcosine, ornithine, etc.), frequently employed three- or four-character codes are employed for residues thereof, including, Sar or Sarc (sarcosine, i.e. N-methylglycine), 15 Aib (α-aminoisobutyric acid), Dab (2,4-diaminobutanoic acid), Dapa (2,3-diaminopropanoic acid), γ-Glu (γ-glutamic acid), Gaba (γ-amînobutanoic acid), β-Pro (pyrrolidine-3-carboxylic acid), and 8Ado (8-amino-3,6-dioxaoctanoic acid), Abu (2-amino butyrîc acid), phPro (β21041 homoproline), PhPhe (β-homophenylalanine) and Bip (β,β diphenylalanine), and Ida (Iminodiacetic acid).

[0063] As is clear to the skilled artisan, the peptide sequences disclosed herein are shown proceeding from left to right, with the left end of the sequence being the N-terminus of the peptide and the right end of the sequence being the C-terminus of the peptide. Among sequences disclosed herein are sequences incorporating a “Hy-” moiety at the amino terminus (N-terminus) of the sequence, and either an “-OH” moiety or an “-NH₂” moiety at the carboxy terminus (C-terminus) ofthe sequence. In such cases, and unless otherwise indicated, a “Hy-” moiety at the N-terminus of the sequence in question indicates a hydrogen atom, corresponding to the presence of a free prîmary or secondary amino group at the N-terminus, while an “-OH” or an “-NH₂” moiety at the C-terminus of the sequence indicates a hydroxy group or an amino group, corresponding to the presence of an amido (CONH₂) group at the C-tenninus, respectively. In each sequence of the invention, a C-termînal “-OH” moiety may be substituted for a C-terminal “-NH₂” moiety, and vice-versa.

[0064] One of skill in the art will appreciate that certain amino acids and other Chemical moietîes are modified when bound to another molécule. For example, an amino acid side chain may be modified when it forms an intramolecular bridge with another amino acid side chain, e.g., one or more hydrogen may be removed or replaced by the bond. According!y, as used herein, reference to an amino acid or modified amino acid présent in a peptide dimer of the présent invention (e.g., at position X4 or position X9) is meant to include the form of such amino acid or modified amino acid présent in the peptide both before and after forming the intramolecular bond.

[0065] The term “dimer,” as used herein, refers broadly to a peptide comprising two or more monomer subunits. Certain dimers comprise two monomer subunits comprising a sequence of Formula (ï) or set forth herein. Dimers of the présent invention include homodimers and heterodimers. A monomer subunit of a dimer may be linked at its C- or N-terminus, or it may be linked via internai amino acid residues. Each monomer subunit of a dimer may be linked through the same site, or each may be linked through a different site (e.g., C-terminus, N-terminus, or internai site).

[0066] The term “NH₂,” as used herein, can refer to a free amino group présent at the amino terminus of a polypeptide. The term “OH,” as used herein, can refer to a free carboxy group présent at the carboxy terminus of a peptide. Further, the term “Ac,” as used herein, refers to Acetyl protection through acylation of the C- or N-terminus of a polypeptide. In certain peptides shown herein, the NH₂ locates at the C-terminus of the peptide indicates an amîno group.

[0067] The term “carboxy,” as used herein, refers to -CO2H.

[0068] The term “isostere replacement,” as used herein, refers to any amino acid or other analog moiety having Chemical and/or structural properties similar to a specified amino acid. In certain embodiments, an isostere replacement is a conservative substitution or an analog of a specified amino acid.

[0069] The term “cyclized,” as used herein, refers to one part of a polypeptide molécule being linked to another part of the polypeptide molécule to form a closed ring, such as by forming a disulfide bridge or thioether bond.

[0070[ The term “subunit,” as used herein, refers to one of a pair of polypeptide monomers that are joined to form a dimer peptide composition.

[0071] The terni “linker moiety,” as used herein, refers broadly to a chemica! structure that is capable of linking or joining together two peptide monomer subunits to form a dimer.

[0072] The term “pharmaceutically acceptable sait,” as used herein, represents salts orzwitterionic forms of the peptides or compounds of the présent invention which are water or oil-soluble or dispersible, which are suitable for treatment of diseases without undue toxicity, irritation, and allergie response; which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use, The salts can be prepared during the final isolation and purification of the compounds or separately by reacting an amino group with a suitable acid. Représentative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycérophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroîodîde, 2hydroxyethansulfonate (isethionate), lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate, and undecanoate. Also, amino groups in the compounds of the présent invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable addition salts include inorganîc acids such as hydrochloric, hydrobromîc, sulfurîc, and phosphoric, and organic acids such as oxalîc, maleîc, succinic, and citric. A pharmaceutically acceptable sait may suitably be a sait chosen, e.g., among acid addition salts and basic salts. Examples of acid addition salts include chloride salts, citrate salts and acetate salts. Examples of basic salts include salts where the cation is selected among alkali métal cations, such as sodium or potassium ions, alkahne earth métal cations, such as calcium or magnésium ions, as well as substituted ammonium ions, such as ions of the type N(R1)(R2)(R3)(R4)+, where RI, R2, R3 and R4 independently will typically designate hydrogen, optionally substituted Cl-6-alkyl or optionally substituted C2-6alkenyl. Examples of relevant Cl-6-alkyl groups include methyl, ethyl, 1-propyl and 2-propyl groups. Examples of C2-6-alkenyl groups of possible relevance include ethenyl, 1 -propenyl and 2-propenyl. Other examples of pharmaceutically acceptable salts are described in “Remington’s Pharmaceutical Sciences”, 17th édition, Alfonso R. Gennaro (Ed.), Mark Pubiishing Company, Easton, PA, USA, 1985 (and more recent éditions thereof), in the “Encyclopaedia of Pharmaceutical Technology”, 3rd édition, James Swarbrick (Ed.), Informa Healthcare USA (Inc.), NY, USA, 2007, and in J. Pharm. Sci. 66: 2 (1977). Also, for a review on suitable salts, see Handbookof Pharmaceutical Salts: Properties, Sélection, and Use by Stahl and Wermuth (WileyVCH, 2002). Other suitable base salts are formed from bases which form non-toxîc salts. Représentative examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnésium, meglumîne, olamine, potassium, sodium, tromethamîne, and zinc salts. Hemîsalts of acids and bases may also be formed, e.g., hemisulphate and hemicalcium salts.

[0073] The term “N(alpha)Methylation”, as used herein, describes the méthylation of the alpha amine of an amino acid, also generally termed as an N-methylation.

[0074] The term “sym méthylation” or “Arg-Me-sym”, as used herein, describes the symmetrical méthylation of the two nitrogens of the guanidine group of arginine. Further, the term “asym méthylation” or “Arg-Me-asym” describes the méthylation of a single nitrogen of the guanidine group of arginine.

[0075] The term “acylating organic compounds”, as used herein refers to various compounds with carboxylic acid functionalîty that are used to acylate theN-terminus of an amino acid or a monomer or dimer, e.g., a monomer subunit prior to forming a C-terminal dimer. Non-limiting examples of acylating organic compounds include cyclopropylacetic acid, 4-Fluorobenzoic acid, 4fluorophenylacetic acid, 3-Phenylpropionîc acid, Succînic acid, Glutaric acid, Cyclopentane carboxylic acid, 3,3,3-trifluoropropeonic acid, 3-Fiuoromethylbutyric acid, Tetrahedro-2H-Pyran4-carboxylic acid.

[0076] The term “alkyl” includes a straight chain or branched, noncyclic or cyclic, saturated alîphatic hydrocarbon containing from 1 to 24 carbon atoms. Représentative saturated straight chain alkyls include, but are not limited to, methyl, ethyl, «-propyl, n-butyl, «-pentyl, «-hexyl, and the 1 ike, while saturated branched alkyls include, without limitation, isopropyl, œc-butyl, isobutyl, ter/-butyl, isopentyl, and the like. Représentative saturated cyclic alkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, while unsaturated cyclic alkyls include, without limitation, cyclopentenyl, cyclohexenyl, and the like.

(0077] Halo or halogen refers to bromo (Br), chloro (Cl), fluoro (F) or iodo (I) substituents. [0078] The tenus “haloalkyl” includes alkyl structures in which at least one hydrogen is replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are ail the same as one another. In other embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not ail the same as one another.

[0079] An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0080] An “aryloxy” group refers to an (aryl)O- group, where aryl is as defined herein.

[0081] “Aminocarbonyl” or “carboxamido” refers to a -CONH2 radical.

[0082] “2-Aminoethoxy” refers to -OCH2CH2-NH2 radical.

]0083] “2-Acetylaminoethoxy” refers to -OCH₂CH2-N(H)C(O)Me radical.

[0084] The term “mammal” refers to any mammalian species such as a human, mouse, rat, dog, cat, hamster, guinea pig, rabbit, livestock, and the like.

[0085] As used herein, a “therapeutically effective amount” of the peptide inhibitor of the invention is meant to descrîbe a sufficient amount of the peptide inhibitor to treat an IL-23/IL23R-related disease, including but not limited to any of the diseases and disorders described herein (for example, to reduce inflammation associated with IBD). In particular embodiments, the therapeutically effective amount will achieve a desired benefit/risk ratio applicable to any medical treatment.

[0086] An “analog” of an amino acid, e.g., a “Phe analog” or a “Tyr analog” means an analog of the referenced amino acid. A varîety of amino acid analogs are known and available in the art, including Phe and Tyr analogs. In certain embodiments, an amino acid analog, e.g., a Phe analog or a Tyr analog comprises one, two, three, four or five substitutions as compared to Phe or Tyr, respectiveîy. In certain embodiments, the substitutions are présent in the side chains of the amino acids. In certain embodiments, a Phe analog has the structure Phe(R²), wherein R² is a Hy, OH, CHj, CO2H, CONH2, CONH2OCH2CH2NH2, /-Bu, OCH2CH2NH2, phenoxy, OCH3, OAllyl, Br, Cl, F, NH2, N3, or guanadino. In certain embodiments, R² is CONH2OCH2CH2NH2, OCH3, CONH2, OCH3 or CO₂H. Examples of Phe analogs include, but are not limited to: hPhe, Phe(4OMe), α-Me-Phe, hPhe(3,4-dimethoxy), Phe(4-CONH₂), Phe(4-phenoxy), Phe(4-guanadino),

Phe(4-tBu), Phe(4-CN), Phe(4-Br), Phe(4-OBzl), Phe(4-NH₂), BhPhe(4-F), Phe(4-F), Phe(3,5

DiF), Phe(CH₂CO₂H), Phe(penta-F), Phe(3_i4-Cl₂)_> Phe (3,4-Fs), Phe(4-CF₃), ββ-diPheAla, Phe(4N₃), Phe[4-(2-aminoethoxy)], 4-Phenylbenzylalanine, Phe(4-CONH₂), Phe(3,4-Dimethoxy), Phe(4-CF₃), Phe(2,3-Ch), and Phe(2,3-F₂). Examples of Tyr analogs include, but are not limited to: hTyr, N-Me-Tyr, Tyr(3-iBu), Tyr(4-N₃) and flhTyr.

PEPTIDE INHIBITORS OF IL-23R

[0087] Genome-wide association studies (GWAS) hâve demonstrated significant association of the IL-23 receptor (IL-23R) gene with inflammatory bowel disease (IBD), suggesting that perturbation of IL-23 sîgnaling could be relevant to the pathogenesis of this disease and other inflammatory diseases and disorders. The présent invention provides compositions and methods to modulatethe IL-23 pathway through antagonism of IL-23R.

[0088] The présent invention relates generally to peptides that hâve IL-23R antagonist activity, including both peptide monomers and peptide dimers. In certain embodiments, this invention demonstrates a new paradigm for treatment of IBD and other diseases and disorders by oral delivery of antagonists of IL-23. IBD represents a local inflammation of the intestinal tissue; therefore, advantageous therapeutîc agents act from the luminal side of the intestine, yielding high drug concentrations in diseased tissue, minimizing systemic availability and resulting in improved efïicacy and safety when compared to systemic approaches. Oral administration of the compounds of the présent invention is expected to maximize drug levels in diseased intestinal tissues while limiting drug concentrations in circulation, thereby providing efficacious, safe, and durable delivery for lîfe-long treatment of IBD and other diseases and disorders.

[0089] In certain embodiments, the présent invention relates to various peptides, or peptide dimers comprising hetero- or homo-monomer subunits, that form cyclized structures through disulfide or other bonds. In certain embodiments, the disulfide or other bonds are intramolecuiar bonds. The cyclized structure of the peptide monomer inhibitors and the monomer subunits of the peptide dimer inhibitors has been shown to increase potency and selectivity of the peptide inhibitors. In certain embodiments, a peptide dimer inhibitor may include one or more intermolecular bonds linking the two monomer peptide subunits within the peptide dimer inhibitor, e.g., an intermolecular bridge between two Pen residues, one in each peptide monomer subunit.

[0090] The présent invention provjdes peptide inhibitors that bind to IL-23R, which may be monomers or dimers. In particular embodiments, the peptide inhibitors inhibit the binding of IL23 to IL-23R. In certain embodiments, the IL-23R is human IL-23R, and the IL-23 is human IL23. In certain embodiments, a peptide inhibitor of the présent invention reduces IL-23 binding to

IL-23R by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least

80%, or at least 90% as compared to a négative control peptide. Methods of determining binding are known in the art and include EL1SA assays, as described in the accompanying Examples.

[0091} In certain embodiments, a peptide inhibitor of the présent invention has an IC50 of > 1 mM, < 1 mM, 500 nM to 1000 nM, < 500 nM, < 250 nM, < 100 nM, < 50 nM, <25 nM, < 10 nM, < 5 nM, < 2 nM, < 1 nM, or < 5 mM, e.g., for inhibiting binding of IL-23 to IL-23R (e.g., human IL23 and human IL-23R). Methods of determining activity are known in the art and include any of those described in the accompanying Examples.

[0092] In certain embodiments, a peptide inhibitor of the présent invention has increased stability, increased gastrointestinal stability, or increased stability in stimulated intestinal fluid (SIF) or simulated gastric fluid (SGF), and/or under redox conditions (e.g., DTT) as compared to a control peptide. In certain embodiments, a control peptide is an unrelated peptide of the same or similar length. In particular embodiments, a control peptide is a peptide having the identîcal or a highly related amino acid sequence (e.g., > 90% sequence identity) as the peptide inhibitor. In particular embodiments, a control peptide is a peptide having the identîcal or a highly related amino acid sequence (e.g., > 90% sequence identity) as the peptide inhibitor, but which does not hâve a cyclized structure, e.g., through an intramolecular bond between two amino acid residues within the control peptide, or which is not dimerized, or which does not comprise a conjugale for stabilization. In particular embodiments, the only différence between the peptide inhibitor and the control peptide is that the peptide inhibitor comprises one or more amino acid substitutions that introduce one or more amino acid residues into the peptide inhibitor, wherein the introduced amino residue(s) forms an intrasulfide disulfîde or thioether bond with another amino acid residue in the peptide inhibitor. One example of a control for a peptide dimer inhibitor îs a monomer having the same sequence as one of the monomer subunits présent in the peptide dimer inhibitor. One example of a control for a peptide inhibitor comprising a conjugate is a peptide having the same sequence but not includîng the conjugated moiety. In certain embodiments, a control peptide is a peptide (e.g., a naturally-occurring peptide) corresponding to a région of IL-23 that binds to IL-23R.

[0093] Methods of determining the stablity of a peptide are known in the art. In certain embodiments, the stability of a peptide inhibitor is determined using an SIF assay, e.g., as described in Example 3. In certain embodiments, the stability of a peptide inhibitor is determined using an SGF assay, e.g., as described in Example 3. In particular embodiments, a peptide inhibitor has a half-life (e.g., in SIF or SGF or DTT) under a given set of conditions (e.g., température) of greater than 1 minute, greater than 10 minutes, greater than 20 minutes, greater than 30 minutes, l 38 greater than 60 minutes, greater than 90 minutes, greater than 120 minutes, greater than 3 hours, or greater than four hours when exposed to SIF or SGF or DTT. In certain embodiments, the température is about 25 °C, about 4 °C, or about 37 °C, and the pH is a physiologîcal pH, or a pH about 7.4.

[0094] In some embodiments, the half-life is measured in vitro using any suitable method known in the art, e.g., in some embodiments, the stabîlity of a peptide of the présent invention is determined by incubating the peptide with pre-warmed human sérum (Sigma) at 37 ⁰ C. Samples are taken at varions time points, typically up to 24 hours, and the stabîlity ofthe sample îs analyzed by separating the peptide or peptide dimer from the sérum proteins and then analyzing for the 10 presence of the peptide or peptide dimer of interest using LC-MS.

[0095] In some embodiments, a peptide inhibitor of the présent invention exhibits improved solubility or reduced aggregation characteristics as compared to a control peptide. Solubility may be determined via any suitable method known in the art. In some embodiments, suitable methods known in the art for determining solubility include incubating peptides in varions buffets (Acetate 15 pH4.0, Acetate pH5.0, Phos/Citrate pH5.0, Phos Citrate pH6.0, Phos pH 6.0, Phos pH 7.0, Phos pH7.5, Strong PBS pH 7.5, Tris pH7.5, Tris pH 8.0, Glycine pH 9.0, Water, Acetic acid (pH 5.0 and other known in the art) and testing for aggregation or solubility using standard techniques. These include, but are not limited to, visual précipitation, dynamic light scatterîng, Circular Dichroism and fluorescent dyes to measure surface hydrophobicîty, and detect aggregation or 20 fibrillation, for example. In some embodiments, improved solubility means the peptide is more soluble in a given liquid than is a control peptide. In some embodiments, reduced aggregation means the peptide has less aggregation in a given liquid under a gîven set of conditions than a control peptide.

(0096] In certain embodiments advantageous for achieving high compound concentrations in 25 intestinal tissues when delivered orally, peptide înhibîtors of the présent invention are stable in the gastrointestinal (GI) environment. Proteolytic metabolism in the GI tract is driven by enzymes (including pepsîns, trypsin, chymotrypsin, elastase, aminopeptidases, and carboxypeptidase A/B) that are secreted from the pancréas into the lumen or are produced as brush border enzymes. Proteases typically cleave peptides and proteins that are in an extended confonnation. In the 30 reducing environment of intestinal fluids, disulfide bonds may be broken, resulting in a linear peptide and rapid proteolysis. This luminal redox environment is largely determined by the Cys/CySS redox cycle. In enterocytes, relevant activities include numerous digestive enzymes such as CYP450 and (JDP-glucuronsyl-transferase. Finally, bacteria, présent in the large intestine at concentration ranging from I0 ⁰ to I0 ² CFU/ml, constitute another metabolic barrier. In certain embodiments, the peptide inhibitors are stable to various pHs that range from strongly acidic in the stomach (pH l ,5-1.9), trending towards basic in the small intestine (pH 6-7.5), and then weakly acidic in the colon (pH 5-7). Such peptide inhibitors are stable during their transit through the various Gl compartments, a process that has been estîmated to take 3-4 h in the intestine and 6-48 h în the colon.

[0097] in some embodiments, the peptide inhibitors ofthe présent invention hâve less dégradation, e.g., over a period of time (i.e., more dégradation stability), e.g., greater than or about 10% less, greater than or about 20% less, greater than or about 30% less, greater than or about 40 less, or greater than or about 50% less dégradation than a control peptide. In some embodiments, dégradation stability is determined via any suitable method known in the art. In some embodiments, the dégradation is enzymatic dégradation. For example, in certain embodiments, the peptide inhibitors hâve reduced susceptibility to dégradation by trypsin, chhrmotrypsin or elastase. In some embodiments, suitable methods known in the art for determinîng dégradation stability include the method described in Hawe et al., J Pharm Sci, VOL. 101, No. 3, 2012, p 895913, incorporated herein in its entirety. Such methods are in some embodiments used to select potent peptide sequences with enhanced shelf lifes. In particular embodiments, peptide stability is determined using a SIF assay or SGF assay, e.g., as described in PCT Publication No. WO 2016/011208.

[0098] ln certain embodiments, peptide inhibitors ofthe présent invention inhibit or reduce IL-23mediated inflammation. In related embodiments, peptide inhibibitors of the présent invention inhibit or reduce IL-23-mediated sécrétion of one or more cytokines, e.g., by binding to IL-23R. on the cell surface, thus inhibiting [L-23 binding to the cell. In particular embodiments, peptide inhibitors ofthe présent invention inhibit or reduce lL-23-mediated activation of Jak2, Tyk2, Statl, Stat3, Stat4, or Stat5. Methods of determinîng inhibition of cytokine sécrétion and inhibition of signaling molécules are known in the art. For example, inhibiton of IL-23/IL-23R. signaling may be determined by measuring inhibition of phospho-Stat3 levels in cell lysâtes, e.g., as described in PCT Publication No. WO 2016/011208.

[0099] In certain embodiments, peptide inhibitors hâve increased redox stability as compared to a control peptide. A variety of assays that may be used to détermine redox stability are known and available in the art. Any of these may be used to détermine the redox stability of peptide inhibitors of the présent invention.

[00100] In certain embodiments, the présent invention provides varions peptide inhibitors that bind or associate with the IL-23R, in vitro or in vivo, to disrupt or block binding between IL-23 and IL23R. In certain embodiments, the peptide inhibitors bind and/or inhibit human IL-23R. In certain embodiments, the peptide inhibitors bind and/or inhibit both human and rodent IL-23R. In certain embodiments, the peptide inhibitors bind and/or inhibit both human and rat IL-23R. In certain embodiments, the peptide inhibitors bind and/or inhibit human IL-23R, rat IL-23R, and cynomolgus monkey IL-23R. In particular embodiments, the peptide inhibitors inhibit rat IL-23R and/or cynomolgus monkey IL-23R at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% as well as they bind or inhibit human IL-23R, e.g., as determined by an assay described herein. In certain embodiments, the peptide inhibitors preferentially bind and/or inhibit human IL-23R and/or rat IL-23R and/or cynomolgus monkey 1L-23R as compared to mouse IL23R. In particular embodiments, the peptide inhibitors preferentially bind to rat IL-23R as compared to mouse IL-23R. In particular embodiments, the peptide inhibitors preferentially bind to human IL-23R as compared to mouse IL-23R. In particular embodiments, the peptide inhibitors preferentially bind to cynomolgus monkey 1L-23R as compared to mouse IL-23R. In certain embodiments, binding of a peptide inhibitor to mouse IL-23R is less than 75%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of binding of the same peptide inhibitor to human IL-23R and/or rat IL-23R and/or cynomolgus monkey IL-23R. In certain embodiments of peptide inhibitors that preferentially bind and/or inhibit human IL-23R and/or rat IL-23R and/or cynomolgus monkey IL-23R as compared to mouse IL-23R, the peptide inhibitor binds to a région of IL-23R that is disrupted by the presence of additional amino acids présent in mouse IL-23R but not human IL-23R or rat IL-23 or cynomolgus monkey 1L-23R. In certain embodiments, the additional amino acids présent in the mouse IL-23R are in the région corresponding to about amino acid residue 315 to about amino acid residue 340 of the mouse IL23R protein, e.g., amino acid région NWQPWSSPFVHQTSQETGKR(SEQ ID NO:447). In particular embodiments, the peptide inhibitors bind to a région of human IL-23R from about amino acid 230 to about amino acid residue 370.

[00101]In certain embodiments, peptide inhibitors show Gl-restrîcted localization following oral administration. In particular embodiments, greater than 50%, greater than 60%, greater than 70%, greater than 80%, or greater than 90% of oral 1 y administered peptide inhibitor is localized to gastrointestinal organs and tissues. In particular embodiments, blood plasma levels of orally administered peptide inhibitor are less than 20%, less than 10%, less than 5%, less than 2%, less

4] than 1% or less than 0.5% the levels of peptide inhibitor round in the small intestine mucosa, colon mucosa, or proximal colon.

[00102] The various peptide inhibitors of the invention may be constructed solely of natural amino acids. Alternatively, the peptide inhibitors may include non-natural amino acids including, but not limited to, modified amino acids. In certain embodiments, modified amino acids include natural amino acids that hâve been chemically modified to include a group, groups, or Chemical moiety not naturally present on the amino acid. The peptide inhibitors of the invention may additionally include one or more D-amino acids. Stïll further, the peptide inhibitors of the invention may include amino acid analogs.

[00103] In certain embodiments, peptide inhibitors of the present invention include one or more modified or unnatural amino acids. In some embodiments of the present invention, a peptide inhibitor includes one or more non-natural amino acids shown in Table 1. In certain embodiments, peptide inhibitors of the present invention include any of those described herein, including but not limited to any of those comprising an amino acid sequence or peptide inhibitor structure shown in any one of the tables herein.

[00104] The present invention also includes any ofthe peptide inhibitors described herein in either a free or a sait form. Thus, embodiments of any of the peptide inhibitors described herein (and related methods of use thereof) include a pharmaceutically acceptable sait of the peptide inhibitor. [00105] The present invention also includes variants of any of the peptide inhibitors described herein, including but not limited to any of those comprising a sequence shown in any one of the tables herein, wherein one or more L-amino acid residue is substituted with the D isomeric form of the amino acid residue, e.g., an L-Ala is substituted with a D-Ala.

[00106] Peptide inhibitors described herein include isotopically-labeled peptide inhibitors. In particular embodiments, the present disclosure provides peptide inhibitors identical to any of those having or recited în the various formulas and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as ²H, ³H, ^l3C, ⁱ⁴C, ^bN, ^l8O, ^l7O, ³⁵S, ^l8F, ³⁶C1, respectively. Certain isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as ³H and ^l4C are incorporated, are useful in drug and/or substrate tissue distribution assays. Furthermore, substitution with isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stabihty, for example increased in vivo half-life or reduced dosage requirements.

[00107] The présent invention also includes any of the peptide monomer inhibitors described herein linked to a linker moiety, including any of the spécifie linker moieties described herein. In particular embodiments, a linker is attached to an N-terminal or C-terminal amino acid, while in other embodiments, a linker is attached to an internai amino acid. In particular embodiments, a linker is attached to two internai amino acids, e.g., an internai amino acid in each of two monomer subunits that form a dimer. In some embodiments of the présent invention, a peptide inhibitor is attached to one or more linker moieties shown.

[00108] The présent invention also includes peptides and peptide dimers comprising a peptide having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to the peptide sequence of a peptide inhibitor described herein. In particular embodiments, peptide inhibitors of the présent invention comprise a core peptide sequence and one or more N-terminal and/or Cterminal modification (e.g., Ac and NH?) and/or one or more conjugated linker moiety and/or halflife extension moiety. As used herein, the core peptide sequence is the amino acid sequence of the peptide absent such modifications and conjugates.

[00109] In certain embodiments, a peptide inhibitor or a monomer subunit of a peptide inhibitor of the présent invention comprises, consists essentially of, or consists of 7 to 35 amino acid residues, 8 to 35 amino acid residues, 9 to 35 amino acid residues, 10 to 35 amino acid residues, 7 to 25 amino acid residues, 8 to 25 amino acid residues, 9 to 25 amino acid residues, 10 to 25 amino acid residues, 7 to 20 amino acid residues, 8 to 20 amino acid residues, 9 to 20 amino acid residues, 10 to 20 amino acid residues, 7 to 18 amino acid residues, 8 to 18 amino acid residues, 9 to 18 amino acid residues, or 10 to 18 amino acid residues, and, optionally, one or more additional non-amino acid moieties, such as a conjugated Chemical moiety, e.g., a PEG or linker moiety. In particular embodiments, a peptide inhibitor of the présent invention (or a monomer subunit thereof), including but not limited to those of any embodiments of Formula 1, is greater than 10, greater than 12, greater than 15, greater than 20, greater than 25, greater than 30 or greater than 35 amino acids, e.g., 35 to 50 amino acids. In certain embodiments, a peptide inhibitor (or a monomer subunit thereof) is less than 50, less than 35, less than 30, less than 25, less than 20, less than 15, less than 12, or less than 10 amino acids. In particular embodiments, a monomer subunit of a peptide inhibitor (or a peptide monomer inhibitor) comprises or consists of 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20,21,22, 23,24,25,26, 27,28,29, 30,31,32,33,34, or 35 amino acid residues. In particular embodiments, a monomer subunit of a peptide inhibitor of the présent invention

I ⁴³ comprises or consists of 10 to 23 amino acid residues and. optionally, one or more additional nonamino acid moieties, such as a conjugated Chemical moiety, e.g., a PEG or linker moiety. In various embodiments, the monomer subunit comprises or consists of 7 to 35 amino acid residues, 7 to 20 amino acid residues, 8 to 20 amino acid residues, 9 to 20 amino acid residues, 10 to 20 amino acid 5 residues, 8 to 18 amino acid residues, 8 to 19 amino acid residues, 8 to 18 amino acîd residues, 9 to 18 amino acid residues, or 10 to 18 amino acid residues. In particular embodiments of any of the varions Formulas described herein.

[001101 Certain illustrative peptide inhibitors described herein comprise 12 or more amino acid residues. However, the present invention also includes peptide inhibitors comprising a fragment 10 of any of the peptide sequences described herein, including peptide inhibitors having 7, 8, 9, 10, or 11 amino acid residues. For example, peptide inhibitors of the present invention include peptides comprising or consisting of X4-X9, X4-X10, X4-X11, X4-X12, X4-X13, X4-XI4, or X4-X15.

[001111 In particular embodiments of the present invention, the amino acid sequences of the peptide inhibitors are not present within an antibody, or are not present within a Vh or Vl région 15 of an antibody.

Peptide Inhibitors

[00112] Peptide inhibitors of the present invention include peptides comprising or consisting of any of the amino acid sequences described herein, compounds having any of the structures described herein, including compounds comprising any of the peptide sequences described herein, and 20 dimers of any of such peptides and compounds. Illustrative peptides of the invention comprise an amino acid sequence or structure described in any of the accompanying tables.

[00113] In a first aspect, the present invention provides a monocyclic peptide inhibitor of an interleukin-23 receptor, or a pharmaceutically acceptable sait thereof, wherein the peptide inhibitor comprises an amino acid sequence of Formula (I):

X3-X4-X5-X6-X7-X8-X9-X10-X11 -X12-X13-X14-X15-X16 (I) wherein

X3 is absent or any amino acid;

X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide);

X5 is Cit, Glu, Gly, substituted Gly, Leu, Ile, beta-Ala, Ala, Lys, Asn, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gin, or Asp;

X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alphaMeAsn, alpha-MeThr, alpha-MeSer, or Val;

X7 is unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

X8 is Gin, alpha-MeLys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, substituted Phe, Tyr, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), l-Nal, 2-Nal, Lys(b-Ala), Lys(Gly), Lys(Benzyl, Ac), Lys(butyl, Ac), Lys(isobutyl,Ac), Lys(propyl,Ac), or Trp;

X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide);

X] 0 is Tyr, or substituted Tyr, unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamido, 2-aminoethoxy, or 2acetylaminoethoxy; and

X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, l -Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X12 is 4-amino-4-carboxy-tetrahydropyran (THP), Acvc, alpha-MeLys, alpha-MeLeu, alphaMeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, cyclohexylAla, Lys, or Aib;

X13 is any amino acid;

X14 is any amino acid;

and

i) XI5 is any amino acid other than His, (D)His, substituted or unsubstituted His, 2Pal, 3Pal, or 4Pal; Xl6 is Sarc, aMeLeu, (D)NMeTyr, His, (D)Thr, bAla, Pro, or (D)Pro; and the peptide inhibitor is other than

Ac-[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-NaIJ-[THP]-[Lys(Ac)]-NNPG-NH₂;

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu][Lys(Ac)]-NN-[Sarc]-NH₂;

Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal][a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂; or

Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[Aib]-[bA]-NH₂;

or ii) Xl5 is His, (D)His, substituted or unsubstituted His, 2Pal, 3Pal, 4Pal, 4TriazolAla, or 5Pyal; and XI6 is absent, (D)aMeTyr, (D)NMeTyr or any amino acid other than THP, substituted or unsubstituted Phe, substituted or unsubstituted (D)Phe, substituted or unsubstituted His, substituted or unsubstituted (D)His, substituted or unsubstituted Trp, substituted or unsubstituted 2-Nal, or N-substituted Asp; and the compound is other than

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-NH₂;

wherein 2Pal is 2-pyridyl substituted alanine, and 3Pal is 3-pyridy 1 substituted alanine, and 4Pal is 4-pyridy 1 substituted alanine

wherein X4 and X9 form a disulfide bond or a thioether bond;

and wherein the peptide inhibitor înhîbits the binding of an înterleukin-23 (IL-23) to an IL-23 receptor.

[00114] In certain embodiments, the présent invention provides a monocyclic peptide inhibitor of an interleukin-23 receptor, or a pharmaceutically acceptable sait or solvaté thereof, wherein the peptide inhibitor comprises or consists of an amino acid sequence of Formula (I):

X3-X4-X5-X6-X7-X8-X9-XI0-X11-X12-X13-X14-X15-X16 (I) wherein

X3 is absent or any amino acid;

X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide);

X5 is Cit, Glu, Gly, Leu, Ile, beta-Ala, Ala, Lys, Asn, Pro, Ser, alpha-MeGIn, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gin, or Asp;

X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGIn, alpha-MeLys, alpha-MeLeu, alphaMeAsn, alpha-MeThr, alpha-MeSer, or Val;

X7 is unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

X8 is Gin, alpha-MeLys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, Asn, Thr, Val, Aib, alpha-MeGIn, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), l-Nal, 2-Nal, Lys(b-Ala), Lys(Gly), or Trp;

X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide);

XIO is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and

XI1 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, I-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; XI2 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, cyclohexylAla, Lys, or Aib;

X13 is any amino acid;

X14 is any amino acid;

and

i) X15 is any amino acid other than His, (D)His, substituted or unsubstituted His, 2Pal, 3Pal, or 4Pal; X16 is Sarc, aMeLeu, (D)NMeTyr, His, (D)Thr, bAla, Pro, or (D)Pro; and the peptide inhibitor is other than

Ac-[Abu]-QTWQC]-[Phe[4-(2-ammoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NNPG-NH₂;

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu][Ly s(Ac)] -NN-[Sarc] -NH₂ ;

Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal][a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂; or

Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[Aib]-[bA]-NH₂;

or ii) X15 is His, (D)His, substituted or unsubstituted His, 2Pal, 3Pal, 4Pal, or 5Pyal; and X16 is absent, (D)aMeTyr, (D)NMeTyr or any amino acid other than THP, substituted or unsubstituted Phe, substituted or unsubstituted (D)Phe, substituted or unsubstituted His, substituted or unsubstituted (D)His, substituted or unsubstituted Trp, substituted or unsubstituted 2-Nal, or Nsubstituted Asp; and the compound is other than

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-NH2;

wherein 2Pal is 2-pyridyl substituted alanine, and 3 Pal is 3-pyndyl substituted alanine, and 4Pal is 4-pyridyl substituted alanine

5Pyal is 5-pyrimidine substituted alanine:

O

wherein X4 and X9 form a disulfïde bond or a thioether bond;

and wherein the peptide inhibitor inhibits the bindîng of an interleukin-23 (IL-23) to an IL-23 receptor.

[00115] In certain embodiments, the présent invention provides a monocyclic peptide inhibitor of an interleukin-23 receptor, or a pharmaceutically acceptable sait or solvaté thereof, wherein the peptide inhibitor comprises or consists of an amino acid sequence of Formula (I):

X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-XI4-X15-X16 (I) wherein

X3 is absent or any amino acid;

X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfbxide);

X5 îs any amino acid;

X6 is any amino acid;

X7 is unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

X8 is any amino acid;

X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen or Pen(sulfoxide);

X10 is unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, carboxy, carboxamido, 2-aminoethoxy, or 2-acetylaminoethoxy; and

X11 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, I -Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy;

X12 is any amino acid;

each XI3, and XI4 is independently any amino acid;

and ) 48

i) Xl5 is any amino acid other than His, (D)His, or substituted or unsubstituted His, 2Pal, 3Pal, or 4Pal; XI6 is Sarc, aMeLeu, (D)NMeTyr, His, (D)Thr, bAla, Pro, or (D)Pro; and the compound is other than

Ac-[Abu]-QTWQC]-[Phe[4-(2-amînoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NNPG-NH₂;

Ac-[Pen ]-N-T-W-[Lys(Ac)]~ [Pen]-Phe [4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu][Lys(Ac)]-NN-[Sarc]-NH₂;

Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal][a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂; or

Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]I0 [Lys(Ac)]-N-[Aib]-[bA)-NH₂;

or ii) XI 5 is His, (D)His, or substituted or unsubstituted His, 2Pal, 3Pal, 4Pal, or 5Pyal; and XI6 is absent, (D)aMeTyr, (D)NMeTyr or any amino acid other than THP, substituted or unsubstituted Phe, substituted or unsubstituted (D)Phe, substituted or unsubstituted His, substituted or unsubstituted (D)His, substituted or unsubstituted Trp, substituted or unsubstituted 2-Nal, or Nsubstituted Asp; and the peptide inhibitor is other than

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-amînoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-NH₂;

wherein 2Pal is 2-pyridyl substituted alanine, and 3Pal is 3-pyridyl substituted alanine, and 4Pal 20 is 4-pyridyl substituted alanine

O O î y OH γΌΗ [| là ^{OH NH}2 _n NH₂ n J nh₂ .._d .. , (2Pal), (3Pal), or (4Pal); and

5Pyal is 5-pyrîmidine substituted alanine:

O

M .

and wherein X4 and X9 form a disulfide bond, or a thîoether bond;

and wherein the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor.

[00116] m certain embodiments, X15 is any amino acid other than His, (D)His, or substituted or unsubstituted His, 2Pal, 3Pal, or4Pal; X16 is Sarc, aMeLeu, (D)NMeTyr, His, (D)Thr, bAla, Pro, or (D)Pro; and the peptide inhibitor is other than

Ac-[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NNPG-NH2;

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]' [Lys(Ac)]-NN-[Sarc]-NH2;

Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal][a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2; or Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[Aib]-[bA]-NH₂.

[00117] In certain embodiments, X15 is His, (D)His, or substituted or unsubstituted His, 2Pal, 3Pal, 4Pal, or 5Pyal; and X16 is absent, (D)aMeTyr, (D)NMeTyr or any amino acid other than THP, substituted or unsubstituted Phe, substituted or unsubstituted (D)Phe, substituted or unsubstituted His, substituted or unsubstituted (D)His, substituted or unsubstituted Trp, substituted or unsubstituted 2-Nal, or N-substituted Asp.

[00118] In certain embodiments, X15 îs 2Pal, 3Pal, or 4Pal; and XI6 is Sarc, aMeLeu, (D)Thr, bAla, Pro, or (D)Pro. In certain embodiments, X15 is 2Pal, 3Pal, or 4Pal; and X16 is Sarc. In certain embodiments, XI 5 is 2Pal, 3Pal, or 4Pal; and X16 is absent.

[00119] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of Formula (la):

X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-Sarc (la) wherein X4 and X9 form a disulfide bond or a thioether bond.

[OOÏ2O]In certain embodiments, the peptide inhibitor comprises an amino acid sequence of Formula (Ib)

X3-X4-X5-X6-X7-X8-X9-X10-X 11 -X12-X13-X 14-X 15-(D)NMeTyr (Ib) wherein X4 and X9 form a disulfide bond or a thioether bond.

[00121] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of Formula (le):

X3-X4-X5-X6-X7-X8-X9-X10-X11 -X12-X 13-X 14-[Pal]-X 16 (le) wherein Pal is 2Pal, 3Pal, or4Pal; XI6 is absent;

wherein 2Pal is 2-pyridyl substituted alanine, and 3Pal is 3-pyridyl substituted alanine, and 4Pal is 4-pyridyl substituted alanine

and X4 and X9 form a disulfïde bond or a thioether bond.

[00122] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of Formula (Id):

X3-X4-X5-X6-X7-X8-X9-X10-X1 l-X12-X13-X14-[His’]-X16 (Id) wherein His’ is His or 3-MeHis; X16 is absent; and X4 and X9 form a disulfïde bond or a thioether bond.

[00123] In certain embodiments, X15 is any amino acid; X16 îs bA, aMe(D)Tyr, (D)NMeTyr, Sarc, Pro, or (D)Pro; and the peptide inhibitor is other than

Ac-[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NNPG-NH2;

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu][Lys(Ac)]-NN-[Sarc]-NH₂;

Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal][a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂; or

Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)H2-NalHa-MeLys][Lys(Ac)]-N-[Aib]-[bA]-NH₂.

[00124] In certain embodiments, XI5 is any amino acid; X16 is bA, aMe(D)Tyr, (D)NMeTyr, Sarc, Pro, or (D)Pro, and the peptide inhibitor is other than

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu][Lys(Ac)]-NN-[Sarc]-NH₂; or

Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal][a-MeLys] - [Ly s(Ac)] -N-[(D)Ly s]-[ Sarc] -NH₂.

[00125] In certain embodiments, XI5 is 3Quin, His, (D)His, 3-Pal, or4-Pal; and XI6 is (D)NMeTyr or Sarc. In certain embodiments, X15 is 3Quin, His, (D)His, 3-Pal, or 4-Pal; and XI6 is (D)NMeTyr. In certain embodiments, XI5 is 3Quin, His, (D)His, 3-Pal, or4-Pal; and X16 is Sarc. [00126] In certain embodiments, X15 is any amino acid; X16 is (D)NMeTyr, or Sarc; and the peptide inhibitor is other than

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu][Lys(Ac)]-NN-[Sarc]-NH₂; or

5I

Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal][a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2.

[00127] In certain embodiments, X15 is 3Quîn, Asn, His, (D)His, (D)Leu, (D)Lys, 3-Pal, 4-Pal, Phe, substituted Phe, (D)Thr, substituted Trp or (D)Val; X16 is (D)NMeTyr, or Sarc; and the peptide inhibitor is other than

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu][Lys(Ac)]-NN-[Sarc]-NH₂; or

Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal][a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂.

[00128] In certain embodiments, X16 is (D)NMeTyr.

[00129] In certain embodiments, X16 is Sarc; and the peptide inhibitor is other than

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu][Lys(Ac)]-NN-[Sarc]-NH₂;

Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-ammoethoxy)]-[2-Nal][a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂;

[00130] In certain embodiments, X15 is His, (D)Lys, 3-Pal, or 4-Pal; X16 is (D)NMeTyr, or Sarc; and the peptide inhibitor is other than

Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal][a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂.

[00131] In certain embodiments, X15 is Asn, His, (D), His, (D)Leu, (D)Lys, 3-Pal, substituted or unsubstîtuted Phe, (D)Thr, or (D)Val; X16 is (D)NMeTyr.

[001321 In certain embodiments, X15 is 3Quin, Asn, His, (D)His, (D)Leu, (D)Lys, 3-Pal, 4-Pal, or substituted Trp; X16 is Sarc; and the peptide inhibitor is other than

Ac-[Pen]“N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu][Lys(Ac)]-NN-[Sarc]-NH₂; or

Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal][a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂.

[00133]In certain embodiments, X15 is (3-Me)His, 3-Pal, or 4-Pal; and XI6 is absent, Sarc or (D)NMeTyr. In certain embodiments, XI5 is (3-Me)His or 3-Pal; and XI6 is absent or Sarc.

[00134] In certain embodiments, X15 is 3-Pal; and X16 is Sarc.

[00135)In certain embodiments, XI5 is Asn, His, (D)Lys, or 3-Pal; X16 is (D)NMeTyr, or Sarc; and the peptide inhibitor is other than

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu][Lys(Ac)]-NN-[Sarc]-NH₂; or

Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4~(2-aminoethoxy)]-[2-Nal][a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂.

[00136]In certain embodiments, XI5 is 5-Pyal, (D)His, (l-Me)His, (3-Me)His, 2-Pal or 3-Pal; and X16 is absent; and the peptide inhibitor is other than:

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-NH₂.

[00137] In certain embodiments, XI5 is 5-Pyal, (l-Me)I-Iis, or (3-Me)His; and X16 is absent.

[00138] In certain embodiments, XI5 îs 5-Pyal or (3-Me)His; and X16 is absent.

[00139] In certain embodiments, X4 or X9 is Cys, (D)Cys, alpha-MeCys, (D)Pen, or Pen; and the bond between X4 and X9 is a disulfide bond.

[00140] In certain embodiments, X4 is Cys, (D)Cys, or alpha-MeCys.

[00141] In certain embodiments, X4 is (D)Pen, Pen, or Pen(sulfoxide).

[00142] In certain embodiments, X4 is Pen. In certain embodiments, X4 is Abu.

[00143] In certain embodiments, X9 is Cys, (D)Cys, or alpha-MeCys.

[00144] In certain embodiments, X9 is Pen or (D)Pen.

[00145] In certain embodiments, X9 is Pen.

[00146] In certain embodiments, X4 is Pen and X9 is Pen, and the bond is a disulfide bond.

[00147] In certain embodiments, X4 is Pen and X9 is Cys, and the bond is a disulfide bond.

[00148] In certain embodiments, X4 or X9 is Abu; and the bond between X4 and X9 is a thioether bond.

[00149] In certain embodiments, X4 is Abu, and X9 is Cys, (D)Cys, or alpha-MeCys. In certain embodiments, X9 is Pen or (D)Pen. In a particular embodiment, X9 is Pen. In a more particular embodiment, X9 is Cys. In a most particular embodiment, X4 îs Abu, and X9 is Cys.

[00150] In certain embodiments, X4 is Abu and X9 is Cys or Pen, and the bond is a thioether bond.

[00151] In certain embodiments, X4 is Abu and X9 is Cys, and the bond is a thioether bond.

[00152] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of Formula (lia), (llb), or (Ile):

Pen-X5-X6-X7-X8-Pen-X 10-X11 -X12-X13-X14-X15-X 16 (Ha), Abu-X5-X6-X7-X8-Cys-Xl 0-X11 -XI 2-X 13-X14-X15-X 16 (llb), or

Abu-X5-X6-X7-X8-Pen-X 10-X 11 -X12-X 13-X 14-X15-X 16 (Ile), wherein X5-X8 and X10-XI4 are as described for Formula (l); Xl5 is His, (D)His, or substituted or unsubstituted His, 2Pal, 3Pal, or 4Pal, and X16 is any amino acid; or XI5 is any amino acid and X16 is Sarc; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or the peptide inhibitor îs cyclized via a Abu-Cys or Abu-Pen thioether bond.

[00153] In certain embodiments, X15 is 2Pal, 3Pal, or 4Pal, and X16 is any amino acid.

[00154] In certain embodiments, X15 is any amino acid and X16 is Sarc.

[00155] In certain embodiments, X15 is any amino acid and XI6 is (D)NMeTyr.

[00156] In certain embodiments, X15 is His or 3MeHis; and X16 is any amino acid.

[00157] In certain embodiments, X5 is Asn, Ser, Gin, or Glu.

[00158] In certain embodiments, X5 is Asn, or Gin.

[00159] In certain embodiments, X5 is Asn. In certain embodiments, X5 îs Ser.

[00160] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of Formula (Ilia), (Illb), (IIIc), or (Hld):

Pen- Asn-X6-X7-X8-Pen-X10-Xl l-X12-X!3-X14-[Pal]-X16 (Ilia), Pen-Gln-X6-X7-X8-Pen-X10-Xl l-X12-X13-X14-[Pal]-X16 (Illb), Abu- Asn-X6-X7-X8-Cys-XI0-Xl l-X12-X13-X14-[Pal]-X16 (IIIc), or

Abu-Gln-X6-X7-X8-Pen-X10-Xl l-XI2-X13-X14-[Pal]-X16 (Illd), wherein X6-X8 and XI 0-X 14 are as described for Formula (I); Pal is 2Pal, 3Pal, or 4Pal; and X16 is any amino acid;

wherein 2Pal is 2-pyridyl substituted alanine, and 3Pal is 3-pyridy 1 substituted alanine, and 4Pal is 4-pyridyl substituted alanine

and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or a Abu-Cys or Abu-Pen thioether bond.

[00161] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of Formula (IVa), (IVb), (IVc), or (IVd), (IVe), (IVf), (IVg), or (IVh):

Pen- Asn-X6-X7-X8-Pen-X 10-X 11 -X12-X13-X 14-X15-Sarc (IVa), Pen-Gln-X6-X7-X8-Pen-X 10-X 11-X 12-X 13-X 14-X15-Sarc (IVb), Abu- Asn-X6-X7-X8-Cys-X10-Xl 1-X 12-XI 3-X 14-X15-Sarc (IVc), Abu-Gln-X6-X7-X8-Pen-X 10-X 11 -XI 2-X 13-X14-X15-Sarc (IVd), Pen- Asn-X6-X7-X8-Pen-Xl 0-XII -X12-X 13-X 14-X15-(D)NMeTyr (IVe),

Pen-Gln-X6-X7-X8-Pen-X10-XI l-X12-X13-X14-X15-(D)NMeTyr (IVf),

Abu- Asn-X6-X7-X8-Cys-XI 0-X1 l-X12-X13-X14-X15-(D)NMeTyr (IVg), or Abu-Gln-X6-X7-X8-Pen-X10-Xl 1-X12-X13-X14-X 15-(D)NMeTyr (IVh), wherein X6-X8 and X 10-X 14 are as described for Formula (I); X15 is any amino acid; and the peptide inhibitor is cyclîzed via a Pen-Pen disulfide bond; or a Abu-Cys or Abu-Pen thioether bond.

[00162] In certain embodiments, X6 is Thr.

[00163] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of Formula (Va), (Vb), (Vc), or (Vd):

Pen- Asn-Thr-X7-X8-Pen-X 10-X 1 l-X12-X13-X14-[Pal]-X16 (Va),

Pen-Gln-Thr-X7-X8-Pen-X10-Xll-X12-X13-X14-[Pal]-Xl6 (Vb),

Abu- Asn-Thr-X7-X8-Cys-X 10-X 11 -X12-X13-X 14-[Pal]-X 16 (Vc), or Abu-Gln-Thr-X7-X8-Pen-Xl 0-X 11 -X i 2-X13-X14-[Pal]-X 16 (Vd), wherein X7-X8 and X10-X 14 are as described for Formula (I); Pal is 2Pal, 3Pal, or 4Pal; and X16 is any amino acid;

wherein 2Pal is 2-pyridyI substituted alanine, and 3Pai is 3-pyridyl substituted alanine, and 4Pal is 4-pyridyl substituted alanine

and the peptide inhibitor is cyclîzed via a Pen-Pen disulfide bond; or a Abu-Cys or Abu-Pen thioether bond.

[00164] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of Formula (Vie), (Vif), (VIg), or (Vlh):

Pen- Asn-Thr-X7-X8-Pen-Xl 0-X 11 -X12-X13-X14-X15-Sarc (Via), Pen-Gln-Thr-X7-X8-Pen-X 10-X 11 -X12-X 13-X 14-Xi 5-Sarc (VIb), Abu- Asn-Thr-X7-X8-Cys-X 10-X 11-X12-X 13-X 14-X 15-Sarc (Vie), Abu-Gln-Thr-X7-X8-Pen-X 10-X 11 -X12-X13-X 14-X 15-Sarc (VId), Pen- Asn-Thr-X7-X8-Pen-X 10-X 11 -X12-X 13-X 14-X 15-(D)NMeTyr (Vie), Pen-Gln-Thr-X7-X8-Pen-Xl 0-X 11 -XI 2-X 13-X 14-X 15-(D)NMeTyr (Vif), Abu- Asn-Thr-X7-X8-Cys-X10-Xl I-X12-X13-X14-X15-(D)NMeTyr (VIg), or Abu-Gln-Thr-X7-X8-Pen-X 10-X 11 -X12-X 13-X 14-X 15-(D)NMeTyr (Vlh), wherein X7-X8 and X10-X14 are as described for Formula (I); X15 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfïde bond; or a Abu-Cys or Abu-Pen thioether bond.

[00165] In certain embodiments, X8 is Gin, alpha-Me-Lys, alpha-MeLys(Ac), Lys(Ac), or Glu. [00166] In certain embodiments, X8 is Gin. In certain embodiments, X8 is Lys(Ac).

[00167] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of Formula (Vlla), (Vllb), (Vile), or (Vlld):

Pen- Asn-Thr-X7-Gln-Pen-X 10-X 1 1 -X12-X13-X14-[Pal]-Xl 6 (Vlla), Pen-Gln-Thr-X7-Gln-Pen-X 10-X 11 -X12-X 13-X 14-[Pal]-X 16 (VIIb), Abu- Asn-Thr-X7-Gln-Cys-Xl0-Xl 1-XI2-X13-X14-[Pal]-Xl 6 (Vile) (SEQ IDNO:448), or Abu-Gln-Thr-X7-Gln-Pen-X 10-X11-X12-X 13-X 14-[Pa]]-X 16 (Vlld), wherein X7 and XI0-X 14 are as described for Formula (I); Pal is 2Pal, 3Pal, or 4Pal; and XI6 is any amino acid;

wherein 2Pal is 2-pyridyl substituted alanine, and 3Pal is 3-pyrîdyl substituted alanine, and 4Pal is 4-pyridyl substituted alanine

and the peptide inhibitor is cyclized via a Pen-Pen disulfïde bond; or a Abu-Cys or Abu-Pen thioether bond.

[00168] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of

Formula (Villa), (VIHb), (Ville), (Vllld), (Ville), (VUIf), (Vlllg), or (VUIh):

Pen-Asn-Thr-X7-Gln-Pen-Xl 0-X 11 -X12-X13-X14-X15-Sarc (Villa),

Pen-Gln-Thr-X7-Gln-Pen-X10-Xll-X12-X13-X14-X15-Sarc (Vlllb),

Abu-Asn-Thr-X7-Gln-Cys-X 10-X 11-X 12-X13-X 14-X 15-Sarc (Ville) (SEQ IDNO:449),

Abu-Gln-Thr-X7-Gln-Pen-X 10-X 11-X 12-X 13-X 14-X 15-Sarc (Vllld),

Pen-Asn-Thr-X7-Gln-Pen-X 10-X I i -X12-X 13-X 14-X 15-(D)NMeTyr (Ville) (SEQ ID NO:450), Pen-Gln-Thr-X7-Gln-Pen-X 10-X 11 -X12-X 13-X 14-X 15-(D)NMeTyr (VIIIf) (SEQ ID NO:451 ), Abu-Asn-Thr-X7-Gln-Cys-X 10-X II -XI 2-X 13-X14-X 15-(D)NMeTyr (VII Ig) (SEQ ID

NO:452), or

Abu-Gln-Thr-X7-Gln-Pen-X 10-X 11 -XI 2-X 13-X 14-X 15-(D)NMeTyr (Vlllh) (SEQ ID

NO:453), wherein X7 and XIO-X14 are as described for Formula (I); XI5 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or a Abu-Cys or Abu-Pen thioether bond.

[00169] In certain embodiments, XI0 is Phe, Phe[4-(2-amînoethoxy)], Phe[4-(2acetyiaminoethoxy)], or Phe(4-CONH2).

]00170] In certain embodiments, X10 is Phe[4-(2-aminoethoxy)], or Phe[4-(2acetylaminoethoxy)]. In certain embodiments, X10 is Phe[4-(2-amînoethoxy)].

[00171] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of Formula (IXa), (IXb), (IXe), or (IXd):

Pen- Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-Xl l-X12-X13-X!4-[Pal]-X16 (IXa) (SEQ ID NO :454), Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-Xl 1 -X12-X13-X14-[Pal]-Xl 6 (IXb) (SEQ ID NO:455), Abu- Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-Xl l-X12-X13-X14-[Pal]-XI6 (IXe) (SEQ ID NO:456), or

Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-XI l-X12-X13-X14-[Pal]-X16 (IXd) (SEQ ID NO:457), wherein X7, and XI1-X14 are as described for Formula (I); F(4-2-ae) is Phe[4-(2aminoethoxy)]; Pal is 2Pal, 3Pal, or 4Pal; and X16 is any amino acid;

wherein 2PaI is 2-pyridyl substituted alanine, and 3Pal is 3-pyridy 1 substituted alanine, and 4Pal is 4-pyridyl substituted alanine

and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or a Abu-Cys or Abu-Pen thioether bond.

[00172] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of Formula (Xa), (Xb), (Xc), (Xd), (Xe), (XI), (Xg), or (Xh):

Pen- Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-Xl l-X!2-XI3-X14-X15-Sarc (Xa) (SEQ IDNO:458), Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-Xl 1-X12-X13-X14-X15-Sarc (Xb) (SEQ ID NO:459), Abu- Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-X 1 l-XI2-X13-X14-X15-Sarc (Xc) (SEQ ID NO:460), Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X l t-Xl 2-XI 3-X14-X15-Sarc (Xd) (SEQ ID NO:461), Pen- Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-Xl 1 -X12-X13-X14-X15-(D)NMeTyr (Xe) (SEQ ID

NO:462),

Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X 11 -XI 2-X 13-X 14-X 15-(D)NMeTyr (Xf) (SEQ ID

NO:463),

Abu- Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-Xl 1 -X12-X13-X14-X15-(D)NMeTyr (Xg) (SEQ ID NO:464), or

Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-XI I-X12-XI3-X14-XI5-(D)NMeTyr (Xh) (SEQ ID NO:465), wherein X7, and XI1-XI4 are as described for Formula (I); F(4-2-ae) is Phe[4-(2aminoethoxy)]; X15 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or a Abu-Cys or Abu-Pen thioether bond.

[00173]In certain embodiments, XI2 îs 4-amîno-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, Ala, cyclohexylAla, Lys, or Aib.

[00174] In certain embodiments, X12 îs 4-amîno-4-carboxy-tetrahydropyran (THP), alpha-MeLys, or alpha-MeLeu.

[00175] In certain embodiments, X12 is alpha-MeLeu. In certain embodiments, X12 is THP.

[00176] In certain embodiments, X13 is Aib, Glu, Cit, Gin, Lys(Ac), alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homoLys(Ac), Lys, pegylated Lys, b-homoGlu, or Lys(Y2-Ac); wherein Y2 is an amino acid. In certain embodiments, X13 is Aib, Glu, Cit, Gin, Lys(Ac), alpha-MeArg, aipha-MeGlu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Lys, or b-homoGlu.

[00177] In certain embodiments, X13 is Glu, Gin, Lys(Ac), or Lys.

[00178] In certain embodiments, X13 is Lys(Ac), or Lys.

[00179] In certain embodiments, X13 is Lys(Ac). In certain embodiments, X13 is Glu.

[00180] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of Formula (Xla), (Xlb), (XIc), or (Xld):

Pen- Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-Xl l-[a-MeLeu]-Lys(Ac)-X14-[Pal]-XI6 (Xla) (SEQ ID NO:466),

Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-Xl l-[a-MeLeu]-Lys(Ac)-X14-[Pal]-X16 (Xlb) (SEQ ID NO:467),

Abu- Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-XI l-[a-MeLeu]-Lys(Ac)-X14-[Pal]-X16 (XIc) (SEQ ID NO:468), or

Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-Xl l-[a-MeLeu]-Lys(Ac)-X14-[Pal]-XI6 (Xld) (SEQ ID

NO:469), wherein X7, XI 1, and XI4, and X14 are as described for Formula (I); F(4-2-ae) is Phe[4-(2aminoethoxy)]; Pal is 2Pal, 3Pal, or 4Pal; and X16 is any amino acid;

I 58 wherein 2Pal is 2-pyridyl substituted alanine, and 3Pal is 3-pyridyI substituted alanine, and 4Pal is 4-pyridyl substituted alanine ⁰⁰ H . ^{N H N} Y Y°^H YY'^Yi^^{0 H NHï} (2Pal), ^NH2 (3Pal),or^N^^ ^NH2 (4Pal);

and the peptide inhibitor is cyclized via a Pen-Pen disulfîde bond; or a Abu-Cys or Abu-Pen 5 thioether bond.

[00181] In certain embodiments, the peptide inhibitor comprises an amino acîd sequence of Formula (Xlla), (Xllb), (XIIc), (Xlld), (Xlle), (Xllf), (Xllg), or (Xllh):

Pen- Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-Xl l-[a-MeLeu]-Lys(Ac)-X14-X] 5-Sarc (Xlla) (SEQ ID NO :470),

Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-Xll-[a-MeLeu]-Lys(Ac)-X14-Xl 5-Sarc (Xllb) (SEQ ID

NO:471),

Abu- Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-Xl l-[a-MeLeu]-Lys(Ac)-X14-XI 5-Sarc (XIIc) (SEQ ID

NO:472),

Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-Xl l-[a-MeLeu]-Lys(Ac)-X14-X15-Sarc (Xlld) (SEQ ID

NO:473),

Pen- Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-Xl l-[a-MeLeu]-Lys(Ac)-XI4-Xl5-(D)NMeTyr (Xlle) (SEQ ID NO:474), Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-Xl l-[a-MeLeu]-Lys(Ac)-Xl4-Xl 5-(D)NMeTyr (Xllf) (SEQ ID NO:475),

Abu- Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-XI l-[a-MeLeu]-Lys(Ac)-X14-X15-(D)NMeTyr (Xllg) (SEQ ID NO:476), or

Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X11 -[a-MeLeu]-Lys(Ac)-X 14-X15-(D)NMeTyr (Xllh) (SEQ 1DNO:477), wherein X7, XI1, and X14 are as described for Formula (I); F(4-2-ae) is Phe[4-(225 aminoethoxy)]; X15 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfîde bond; or a Abu-Cys or Abu-Pen thioether bond.

[00182] In certain embodiments, X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Leu, Ala, (D)Ala, beta-Ala, His, Thr, n-Leu, Gin, Ser, (D)Ser, Tic, Trp, alpha-MeGIn, alpha-MeAsn, alphaMeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys(Ac). In certain embodiments, X14 is Asn, 30 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Ala, (D)Ala, beta-Ala, His, Thr, Gin, Ser, (D)Ser, Tic,

I ⁵⁹

Trp, alpha-MeGIn, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys(Ac).

[00183]In certain embodiments, Xl4 is Asn.

[00184] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of

Formula (XlIIa), (XlIIb), (XIIIc), or (XlIId):

Pen- Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-Xl l-[a-MeLeu]-Lys(Ac)-Asn-[Pal]-XI6 (Xllla) (SEQ ID NO:478),

Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-Xl l-[a-MeLeu]-Lys(Ac)-Asn-[Pal]-X16 (XlIIb) (SEQ ID

NO:479),

Abu- Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-Xl l-[a-MeLeu]-Lys(Ac)-Asn-[Pal]-X16 (XIIIc) (SEQ IDNO:480), or

Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X 11 -[a-MeLeu]-Lys(Ac)-Asn-[Pal]-X 16 (XIIld) (SEQ ID

NO:481), wherein X7 and XI1 are as described for Formula (I); F(4-2-ae) is Phe[4-(2-aminoethoxy)]; Pal is 2Pal, 3Pal, or 4Pal; and X16 is any amino acid; and the peptide inhibitor is cyclized via a PenPen disulfide bond; or a Abu-Cys or Abu-Pen thioether bond.

[00185] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of

Formula (XlVa), (XlVb), (XIVc), (XlVd), (XlVe), (XlVf), (XlVg), or (XlVh):

Pen- Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-Xl l-[a-MeLeu]-Lys(Ac)-Asn-X15-Sarc (XlVa) (SEQ ID

NO:482),

Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-Xl l-[a-MeLeu]-Lys(Ac)-Asn-X15-Sarc (XlVb) (SEQ ID

NO:483),

Abu- Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-Xl l-[a-MeLeu]-Lys(Ac)-Asn-X15-Sarc (XIVc) (SEQ

ID NO:484),

Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X 11 -[a-MeLeu]-Lys(Ac)-Asn-X 15-Sarc (XlVd) (SEQ ID

NO:485),

Pen- Asn-Thr-X7-Gln-Pen-[F(4-2ae)]-Xl l-[a-MeLeu]-Lys(Ac)-Asn-X15-(D)NMeTyr (XI Ve) (SEQ ID NO:486),

Pen-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-X 11 -[a-MeLeu]-Lys(Ac)-Asn-X I5-(D)NMeTyr (XIVf) (SEQ ID NO:487),

Abu- Asn-Thr-X7-Gln-Cys-[F(4-2ae)]-Xl 1-[a-MeLeu]-Lys(Ac)-Asn-X 15-(D)NMeTyr (XIVg) (SEQ ID NO:488), or ) 60

Abu-Gln-Thr-X7-Gln-Pen-[F(4-2ae)]-Xl l-[a-MeLeu]-Lys(Ac)-Asn-Xl5-(D)NMeTyr (XI Vh) (SEQ ID NO:489), wherein X7 and XI l are as described for Formula (I); F(4-2-ae) is Phe[4-(2-aminoethoxy)]; XI5 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or a Abu5 Cys or Abu-Pen thioether bond.

[00186] In certain embodiments, X7 is unsubstituted Trp.

[00187] In certain embodiments, X7 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; and XI1 is as described for Formula (I).

[00188] In certain embodiments, X7 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, 10 or alkoxy; and the substitution is at 4-, 5-, 6- or 7- position.

[00189] In certain embodiments, X7 is Trp substituted with cyano, F, Cl, Br, I, Me, Et, i-Pr, n-Pr, n-Bu, t-Bu, CF3, hydroxy, OMe, or OEt; and the substitution îs at 4-, 5-, 6- or 7- position.

[00190] In certain embodiments, X7 is Trp substituted with 5-F, 6-F, 7-F, 5- Cl, 6-CI, 7-CI, 5-Me, 6-Me, 7-Me, 5-OH, 6-OI-I, 7-OH, 5-OMe, 6-OMe, or 7-OMe.

[00191] In certain embodiments, X7 is Trp substituted with 7-Me, 5-F, 7-F, 6-CI, 6-Me, 4-OMe, 5OMe, or 5-Br.

[00192] In certain embodiments, X7 is Trp substituted with 7-Me, 6-Me, 4-OMe, or 6-CI.

[00193] In certain embodiments, X7 is Trp substituted with 7-Me.

[00194] In certain embodiments, X7 is Trp substituted with phenyl, substituted phenyl, or thienyl.

[00195] In certain embodiments, X7 is Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, phenyl, substituted phenyl, or thienyl.

[00196] In certain embodiments, X7 is Trp substituted with i) phenyl, unsubstituted or substituted with cyano, halo, alkyl, haloalkyl, aryl hydroxy, alkoxy, or haloalkoxy; or ii) thienyl.

[00197] In certain embodiments, X7 is Trp substituted with phenyl, unsubstituted or substituted 25 with Me, Et, 11-Pr, i-Pr, t-Bu, OMe, OEt, Cl, F, CF3, OCF3, phenyl, substituted phenyl, or amido.

[00198] In certain embodiments, X7 is Trp substituted with 7-Me. [n certain embodiments, X7 is Trp substituted with 7-Ph.

[00199] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of Formula (XVa), (XVb), (XVc), or (XVd):

Pen- Asn-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-Xl l-[a-MeLeu]-Lys(Ac)-Asn-[Pal]-X16 (XVa) (SEQ ID 190:490),

Pen-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-X 11 -[a-MeLeu]-Lys(Ac)-Asn-[Pal]-X 16 (XVb) (SEQ ID NO:491),

Abu- Asn-Thr-[W(7-Me)]-Gm-Cys-[F(4-2ae)]-Xl l-[a-MeLeu]-Lys(Ac)-Asn-[Pal]-Xl6 (XVc) (SEQ ID NO:492), or

Abu-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-X 11 -[a-MeLeu]-Lys(Ac)-Asn-[Pal]-X 16 (XVd) (SEQ ID NO:493), wherein XI I is as described for Formula (I); F(4-2-ae) is Phe[4-(2-aminoethoxy)]; Pat is 2Pal, 3Pal, or 4Pal; and Xl6 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or a Abu-Cys or Abu-Pen thioether bond.

[00200] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of Formula (XVIa), (XVIb), (XVIc), (XVld), (XVIe), (XVIf), (XVIg), or (XVIh):

Pen- Asn-Thr-fW(7-Me)]-Gln-Pen-[F(4-2ae)]-Xl i-[a-MeLeu]-Lys(Ac)-Asn-X 15-Sarc (XVIa) (SEQ ID NO :494),

Pen-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-Xl l-[a-MeLeu]-Lys(Ac)-Asn-Xl 5-Sarc (XVIb) (SEQ ID NO:495),

Abu- Asn-Thr-[W(7-Me)]-Gln-Cys-[F(4-2ae)]-Xl l-[a-MeLeu]-Lys(Ac)-Asn-Xl 5-Sarc (XVIc) (SEQ ID NO:496),

Abu-Gln-Thr-[W(7-Me)]-Gîn-Pen-[F(4-2ae)]-XU-[a-MeLeu]-Lys(Ac)-Asn-Xl 5-Sarc (XVld) (SEQ 1DNO:497),

Pen- Asn-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-Xl I-[a-MeLeu]-Lys(Ac)-Asn-X 15-(D)NMeTyr (XVIe) (SEQ ID NO:498),

Pen-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-Xl l-[a-MeLeu]-Lys(Ac)-Asn-X15-(D)NMeTyr (XVIf) (SEQ ID NO:499),

Abu- Asn-Thr-(W(7-Me)]-Gln-Cys-[F(4-2ae)]-Xl l -[a-MeLeu]-Lys(Ac)-Asn-X 15-(D)NMeTyr (XVIg) (SEQ ID NO:500), or

Abu-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-Xl 1-[a-MeLeu]-Lys(Ac)-Asn-X15-(D)NMeTyr (XVIh) (SEQ ID NO:501), wherein XI1 is as described for Formula (I); F(4-2-ae) is Phe[4-(2-aininoethoxy)]; X15 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or a Abu-Cys or Abu-Pen thioether bond.

[00201] In certain embodiments, XII is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4dimethoxy), or 1-Nal.

[00202] In certain embodiments, XI1 is 2-Nal, or 1-Nal.

[00203]In certain embodiments, XI1 is 2-Nal.

[00204] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of

Formula (XVIIa), (XVIIb), (XVHc), or (XVIId):

Pen- Asn-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-[2-Nal]-[a-MeLeu]-Lys(Ac)-Asn-[Pal]-Xl6 (XVIIa) (SEQ ID NO:502),

Pen-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-[2-Nal]-[a-MeLeu]-Lys(Ac)-Asn-[Pal]-X 16 (XVIIb) (SEQ ID NO:503),

Abu- Asn-Thr-[W(7-Me)]-Gln-Cys-[F(4-2ae)]-[2-Nal]-[a-MeLeu]-Lys(Ac)-Asn-[Pal]-X 16 (XVIIc) (SEQ ID NQ:504), or

Abu-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-[2-Nal]-[a-MeLeu]-Lys(Ac)-Asn-[Pal]-Xl6 (XVIId) (SEQ ID NQ:505), wherein F(4-2-ae) îs Phe[4-(2-aminoethoxy)]; Pal is 2Pal, 3Pal, or 4Pal; and XI6 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfïde bond; or a Abu-Cys or AbuPen thioether bond.

[00205] In certain embodiments, the peptide inhibitor comprises an amino acid sequence of

Formula (XVIIIa), (XVIIIb), (XVIIIc), (XVIIId), (XVUIe), (XVIIIf), (XVIIIg), or (XVIIIh):

Pen- Asn-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-[2-Nal]-[a-MeLeu]-Lys(Ac)-Asn-X 15-Sarc (XVIIIa) (SEQ ID NO:506),

Pen-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-[2-Nal]-[a-MeLeu]-Lys(Ac)-Asn-Xl 5-Sarc (XVIIIb) (SEQ ID NQ:507),

Abu- Asn-Thr-[W(7-Me)]-Gln-Cys-[F(4-2ae)]-[2-Nat]-[a-MeLeu]-Lys(Ac)-Asn-Xl 5-Sarc (XVIIIc) (SEQ IDNO:508),

Abu-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-[2-Nal]-[a-MeLeu]-Lys(Ac)-Asn-Xl 5-Sarc (XVIIId) (SEQ ID NO:509),

Pen- Asn-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-[2-Nal]-[a-MeLeu]-Lys(Ac)-Asn-X 15(D)NMeTyr (XVIIIe) (SEQ ID NO:510),

Pen-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-[2-NaI]-[a-MeLeu]-Lys(Ac)-Asn-Xl 5(D)NMeTyr (XVIIIf) (SEQ ID NO:511 ),

Abu- Asn-Thr-[W(7-Me)]-Gln-Cys-[F(4-2ae)]-[2-Nal]-[a-MeLeu]-Lys(Ac)-Asn-X 15(D)NMeTyr (XVIIIg) (SEQ ID NO:512), or

Abu-Gln-Thr-[W(7-Me)]-Gln-Pen-[F(4-2ae)]-[2-Nal]-[a-MeLeu]-Lys(Ac)-Asn-Xl 5(D)NMeTyr (XVIIIh) (SEQ ID NO:513), wherein F(4-2-ae) is Phe[4-(2-aminoethoxy)j; X15 is any amino acid; and the peptide inhibitor is cyclized via a Pen-Pen disulfïde bond; or a Abu-Cys or Abu-Pen thioether bond.

[00206]In certain embodiments, Xl5 is 2Pal, 3 Pal, 4Pal, His, (D)His, Lys, (D)Lys, Leu, (D)Leu, 2Quin, or 3Quin.

[00207]In certain embodiments, Xl5 is 3Pal, 4Pal, His, (D)His, (D)Lys or (D)Leu.

[00208]In certain embodiments, Xl5 is 3Pal, His, (D)Lys or (D)Leu.

[00209] In certain embodiments, X15 is His.

[00210]In certain embodiments, X15 is 3Pal.

[00211]In certain embodiments, XI6 is absent.

[00212] In one particular embodiment, X3 is absent.

[00213] In certain embodiments, with respect to Formula (XVa)-(XVIIIh), W(7-Me) is replaced with W(7-Ph).

[00214] In certain embodiments, with respect to Formula (XVa)-(XVIIIh), W(7-Me) îs replaced with W or unsubstituted Trp.

[00215] In certain embodiments, with respect to Formula (VlJa)-(XVHIh), Gin is replaced with Lys(Ac).

[00216] In certain embodiments, with respect to Formula (Xla)-(XVIIIh), aMeLeu is replaced with THP.

[00217] In certain embodiments, the peptide inhibitor comprises the structure of Formula (Z): R^l-X-R² (Z) or a pharmaceutically acceptable sait thereof, wherein

R¹ is a hydrogen, Ac, a C1-C6 alkyl, a C6-C12 aryl, a C6-CI2 aryl-Cl-6alkyl, a C1-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing; X is the amino acid sequence of Formula (I), (la), (Ib), (le), (Id), or any of Formula (Il)-(XVIIId); and R² is OH, NH₂ or NHMe.

[00218] In certain embodiments, the peptide inhibitor comprises the structure of Formula (Z) R'-X-R² (Z) or a pharmaceutically acceptable sait thereof, wherein

R¹ is a hydrogen, Ac, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12 aryl-Cl-6alkyt, a C1-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing; X is the amino acid sequence of Formula (I), any of Formula (H)-(XVind), or an amino acid sequence set forth in any of Table El; and R² is OH orNH₂.

[00219] In certain embodiments, the peptide inhibitor comprises or consîsts of an amino acid sequence of Formula (Z):

RLX3-X4-X5-X6-X7-X8-X9-X10-X1 1-X12-X13-X 14-X1 5-X16-R² (Z’) or a pharmaceutically acceptable sait thereof, wherein

R¹ is a hydrogen, Ac, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12aryl-Cl-6a[kyl, a CI-C20 alkanoyl, and including PEGylated versions alone or as spacers of any ofthe foregoing; and R² is OH, NH?

or N(H)Me.

[00220] In certain embodiments, the peptide inhibitor comprises or consists of an amino acid of Formula (Z):

R^XS^-XS-XÔ^-XS-XO-XlO-XH-XU-XB-XH-XlS-Xlà-R² (Z’) or a pharmaceutically acceptable sait thereof, wherein

R¹ is a hydrogen, Ac, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12aryl-Cl-6alkyl, a C1-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing; and R² is OH or NHî.

[00221] In certain embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of Formula (Z):

R' -X3-X4-X5-X6-X7-X 8-X9-X10-X11 -X12-X13 -X14-X15 -X16- R² (Z ’ ) or a phannaceutically acceptable sait thereof, wherein

X3 is absent or any amino acid;

X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide);

X5 is Cit, Glu, Gly, substituted Gly, Leu, Ile, beta-Ala, Ala, Lys, Asn, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gin, or Asp;

X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alphaMeAsn, alpha-MeThr, alpha-MeSer, or Val;

X7 is unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

X8 îs Gin, alpha-MeLys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGIn, Cit, Glu, Phe, substituted Phe, Tyr, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-Nal, 2-Nal, Lys(b-Ala), Lys(Gly), Lys(Benzyl, Ac), Lys(butyl, Ac), Lys(isobutyl,Ac), Lys(propyl,Ac), or Trp;

X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide);

X10 is Tyr, or substituted Tyr, unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamido, 2-aminoethoxy, or 2acetylaminoethoxy; and

XI1 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Qutn, 1-Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy; X12 is 4-amino-4-carboxy-tetrahydropyran (THP), Acvc, alpha-MeLys, aipha-MeLeu, alphaMeArg, alpha-MePhe, aipha-MeLeu, alpha-MeLys, alpha-MeAsn, alpha-MeTyr, Ala, cyclohexylAla, Lys, or Aib;

X13 is any amino acid;

X14 îs any amino acid;

and

i) X15 is any amino acid other than His, (D)His, substituted or unsubstituted His, 2Pal, 3Pal, or 4Pal; X16 is Sarc, aMeLeu, (D)NMeTyr, His, (D)Thr, bAla, Pro, or (D)Pro; and the peptide inhibitor is other than

Ac-[Abu]-QTWQC]-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NNPG-NH2; Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu][Lys(Ac)]-NN-[Sarc]-NH₂;

Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal][a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂; or Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLysJ[Lys(Ac)]-N-[Aib]-[bA]-NH₂;

or ii) XI5 is Hîs, (D)Hîs, substituted or unsubstituted His, 2Pal, 3Pal, 4Pal, 4TriazolAla, or 5Pyal; and X16 is absent, (D)aMeTyr, (D)NMeTyr or any amino acid other than THP, substituted or unsubstituted Phe, substituted or unsubstituted (D)Phe, substituted or unsubstituted His, substituted or unsubstituted (D)His, substituted or unsubstituted Trp, substituted or unsubstituted 2-Nal, or N-substituted Asp; and the compound is other than

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-amînoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-NH₂;

wherein 2Pal is 2-pyridy 1 substituted alanine, and 3Pal is 3-pyridy 1 substituted alanine, and 4Pal is 4-pyridyl substituted alanine

5Pyal is 5-pyrimidine substituted alanine:

Ο

wherein Χ4 and Χ9 form a disulfïde bond or a thioether bond; and wherein the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor.

[00222] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) wherein X4 or X9 is Cys, (D)Cys, alpha-MeCys, (D)Pen, or Pen; and the bond between X4 and X9 is a disulfïde bond. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) wherein X4 is (D)Pen, Pen, or Pen(sulfoxide). In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) wherein X4 is Pen. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) wherein X9 is Pen or (D)Pen. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) wherein X9 is Pen. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) wherein X4 is Pen and X9 is Pen, and the bond is a disulfïde bond.

[00223] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) the peptide inhibitor comprises the structure of Formula (Z’):

R'-X3-Pen-X5-X6-X7-X8-Pen-X 10-Xl l -X12-X 13-X 14-X ] 5-X16-R² (Z’-A) wherein the peptide inhibitor is cyclized via a Pen-Pen disulfïde bond.

[00224] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-A) wherein X5 is Asn, Ser, Gin, or Glu. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-A) wherein X5 is Asn.

[00225] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-A) wherein the peptide inhibitor comprises the structure of Formula (Z’):

R^l-X3-Pen-Asn-X6-X7-X8-Pen-Xl0-Xl 1-X12-X13-X14-X15-XI6-R² (Z’-B) wherein the peptide inhibitor is cyclized via a Pen-Pen disulfïde bond.

[00226] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-B) wherein X6 is Asp, or Thr. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-B) wherein X6 is Thr.

[00227] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-B) wherein the peptide inhibitor comprises the structure of Formula (Z’):

R'-X3-Pen-Asn-Thr-X7-X8-Pen-Xl0-Xl 1-X12-X13-X14-X15-XI6-R² (Z’-C) wherein the peptide inhibitor is cyclîzed via a Pen-Pen disulfide bond.

[00228] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-C) wherein X8 is Gin, alpha-Me-Lys, alpha-MeLys(Ac), Lys(Ac), or Glu. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-C) wherein X8 is Cit, Lys(Ac), Lys(Benzyl, Ac), Lys(butyl, Ac), Lys(isobutyl,Ac), Lys(propyl,Ac),Gln, 4adamantyl-Phe, (4-AcNH)Phe, or Tyr. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-C) wherein X8 îs Lys(Ac).

[00229] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-C) wherein the peptide inhibitor comprises the structure of Fonnula (Z’):

R^l-X3-Pen-Asn-Thr-X7-Lys(Ac)-Pen-X 10-X 1 1-X12-X 13-X 14-X 15-X16-R² (Z’-D) wherein the peptide inhibitor is cyclîzed via a Pen-Pen disulfide bond.

[00230J In certain embodiments, the peptide inhibitor is the peptide inhibitor of Fonnula (Z’) to (Z’-D) wherein X10 îs Phe or substituted Phe, Tyr or substituted Tyr. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-D) wherein X10 is Phe or substituted Phe. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-D) wherein X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], or Phe(4-CONH2). In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-D) wherein X10 is Phe[4-(2-aminoethoxy)], or Phe[4-(2-acetylaminoethoxy)]. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-D) wherein X10 is Phe[4-(2-aminoethoxy)].

[00231]In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-D) wherein the peptide inhibitor comprises the structure of Formula (Z’): R'-X3-Pen-Asn-Thr-X7-Lys(Ac)-Pen-[F(4-2ae)]-XI I-X12-X13-X14-X15-X16-R² (Z’-E) (SEQ

ID NO:514) wherein F(4-2-ae) îs Phe[4-(2-aminoethoxy)], and the peptide inhibitor îs cyclîzed via a Pen-Pen disulfide bond.

[00232] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-E) wherein XI1 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), or 1-NaL In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-E) wherein XI1 is 2-Nal, or 1-NaL In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-E) wherein XI1 is 2-NaL

[00233] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Fonnula (Z’) to (Z’-E) wherein the peptide inhibitor comprises the structure of Formula (Z’):

R¹-X3-Pen-Asn-Thr-X7-Lys(Ac)-Pen-[F(4-2ae)]-[2-Nal]-X 12-X i 3-X14-X15-X16-R² (Z’-F) (SEQ IDNO:515) wherein F(4-2-ae) is Phe[4-(2-aminoethoxy)], and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond.

[00234] In certain embodiments, the peptide inhibitor îs the peptide inhibitor of Formula (Z’) to (Z’-F) wherein X12 is 4-amino-4-carboxy-tetrahydropyran (THP), alpha-MeLys, alpha-MeLeu, Ala, cyclohexylAla, Lys, or Aib. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-F) wherein X12 is 4-amîno-4-carboxy-tetrahydropyran (THP), Acpx, Acvc, alpha-MeLys, or alpha-MeLeu. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-F) wherein X12 îs THP.

[00235] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-F) wherein the peptide inhibitor comprises the structure of Formula (Z’):

R'-X3-Pen-Asn-Thr-X7-Lys(Ac)-Pen-[F(4-2ae)]-[2-Nal]-THP-X 13-X14-X15-X 16-R² (Z’-G) (SEQ ID NO:5I6) wherein F(4-2-ae) is Phe[4-(2-aminoethoxy)], and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond.

[00236] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-G) wherein X13 is Aib, Glu, Cit, Gin, Lys(Ac), alpha-MeArg, alpha-MeGlu, alpha-MeLeu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Lys, or bhomoGlu. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-G) wherein XI3 is Aib, Glu, Cit, Gin, Lys(Ac), alpha-MeArg, alpha-MeGlu, alpha-MeLys, alpha-Me-Asn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Lys, or b-homoGlu. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-G) wherein X13 is Glu, Gin, Lys(Ac), or Lys. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’)to (Z’-G) wherein XI3 is alpha-methylGlu, Glu, or Lys(Ac). In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-G) wherein X13 is Glu.

[00237] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-G) wherein the peptide inhibitor comprises the structure of Formula (Z’):

R'-X3-Pen-Asn-Thr-X7-Lys(Ac)-Pen-[F(4-2ae)]-[2-Nal]-THP-Glu-X14-X15-X16-R² (Z’-H) (SEQ IDNO:517) wherein F(4-2-ae) is Phe[4-(2-aminoethoxy)], and the peptide inhibitor îs cyclized via a Pen-Pen disulfide bond.

[00238] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z ) to (Z’-H) wherein XI4 is Asn, 2-Nap, Aib, Arg, Cît, Asp, Phe, Gly, Lys, Leu, Ala, (D)Ala, beta-Ala, His, Thr, n-Leu, Gin, Ser, (D)Ser, Tic, Trp, alpha-MeGln, alpha-MeAsn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys(Ac). In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-H) wherein X14 is Asn, 2-Nap, Aib, Arg, Cit, Asp, Phe, Gly, Lys, Ala, (D)Ala, beta-Ala, His, Thr, Gin, Ser, (D)Ser, Tic, Trp, alpha-MeGln, alphaMeAsn, alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), or Lys(Ac). In certain embodiments, the peptide inhibitor îs the peptide inhibitor of Formula (Z’) to (Z’-H) wherein X14 is Asn.

[00239] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-H) wherein the peptide inhibitor comprises the structure of Formula (Z’):

RLX3-Pen-Asn-Thr-X7-Lys(Ac)-Pen-[F(4-2ae)]-[2-Nal]-THP-Glu-Asn-X15-X16-R² (Z’-I) (SEQ ID NO:518) wherein F(4-2-ae) is Phe[4-(2-aminoethoxy)], and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond.

[00240] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-I) wherein X7 is Trp or Trp substituted with alkyl, or phenyl; and the substitution is at the 4-, 5-, 6- or 7- position. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-I) wherein X7 is Trp or Trp substituted with Me, Et, i-Pr, n-Pr, n-Bu, t-Bu, or phenyl; and the substitution is at the 4-, 5-, 6- or 7- position. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-I) wherein X7 is Trp or Trp substituted with 5-Me, 6-Me, 7-Me, 5-phenyl, 6-phenyl or 7-Ph. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-I) wherein X7 is Trp or Trp substituted with 7-Me, 6-Me, or 7-Ph. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-I) wherein X7 is Trp or Trp substituted with 7-Me or 7-Ph. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-I) wherein X7 is Trp substituted with 7-Me.

[00241] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-I) wherein the peptide inhibitor comprises the structure of Formula (Z’):

R'-X3-Pen-Asn-Thr-[W(7-Me)]-Lys(Ac)-Pen-[F(4-2ae)]-[2-Nal]-TFlP-Glu-Asn-X15-X16-R² (Z’-J)(SEQ ID NO:519) wherein F(4-2-ae) is Phe[4-(2-aminoethoxy)], and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond.

[00242] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z*-J) wherein X3 is absent or(D)Arg. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-J) wherein X3 is absent. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-J) wherein X3 is (D)Arg.

[00243] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-J) wherein the peptide inhibitor comprises the structure of Formula (Z’): R‘-Pen-Asn-Thr-[W(7-Me)]-Lys(Ac)-Pen-[F(4-2ae)]-[2-Nal]-THP-Glu-Asn-XI 5-X16-R² (Z’-K) (SEQ ÏD NO:520) wherein F(4-2-ae) is Phe[4-(2-aminoethoxy)], and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond.

[00244] [n certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-J) wherein X3 is absent or (D)Arg; X4 is Abu, Cys, (D)Cys, alpha-MeCys, or Pen; X5 is Ala, (allyl)Gly, Ile, Leu, Asn, Nie, or Gin; X6 is Asp, or Thr; X7 is (7-methyl)Trp, (4-F)-Trp, or Trp; X8 is Cit, Lys(Ac), Lys(Benzyl, Ac), Lys(butyl, Ac), Lys(isobutyl,Ac), Lys(propyl,Ac),Gln, 4adamantyl-Phe, (4-AcNH)Phe, or Tyr; X9 is Cys, alpha-MeCys, or Pen; X10 is Phe or substituted Phe, Tyr or substituted Tyr; XI1 is 2-Nal; X12 is 4-amino-4-carboxy-tetrahydropyran (THP), Acpx, Acvc, alpha-MeLys, or alpha-MeLeu; X13 is alpha-methylGlu, Glu, or Lys(Ac); and X14 is Asn.

[00245] in certain embodiments, the peptide inhibitor is the peptide inhibitor of Fonnula (Z’) to (Z’-K) wherein R¹ is H or C1-C20 alkanoyl.

[00246] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-K) wherein R¹ is H or Ac.

[00247]In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-K) wherein R¹ is Ac.

[00248] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-K) wherein R² isNH2 orN(H)Me. In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-K) wherein R² is NH2.

[00249] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-K) wherein R¹ is Ac; X3 is absent or (D)Arg; X4 is Pen; X5 is Asn;

X6 is Thr; X7 is Trp or (7-Me)Trp or (7-Ph)Trp; X8 is Lys(Ac); X9 is Pen; XI0 is Phe(2aminoethoxy); Xi 1 is 2-Nal; XI2 is 4-amino-4-carboxy-tetrahydropyran (THP); X13 is Gin; XI4 is Asn; and R² ÎsNH₂ or N(H)Me.

7)

[00250] in certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z^!) to (Z’-K) wherein R¹ is Ac; X3 is absent; X4 is Pen; X5 is Asn;

X6 is Thr; X7 is 7-methylTrp; X8 is Lys(Ac); X9 is Pen; XI0 is Phe(2-aminoethoxy); XI1 is 2Nal; XI2 is 4-amino-4-carboxy-tetrahydropyran (THP); X13 is Glu; XI4 is Asn; and R² is NH₂ or N(H)Me.

[00251) In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-K) wherein X15 is Aib, beta-Ala, (D)Phe, (D)Lys, (D)Leu, (D)0m, substituted (D)Phe, (D)Arg, (D)Val, (D)Tyr, Phe, Hph, Asn, 4-amino-4-carboxy-tetrahydropyran (THP), substituted Tyr, or Tyr; and XI6 is beta-Ala, (D)NMeTyr, (D)Pro, NMeTyr, Pro, or Sarc,

[00252] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-K) wherein X15 is 3Paî, substituted 3Pal, 4Pal, 4-triazole-Ala, (D)His, His or substituted His; and X16 îs absent, Aib, aipha-MePro, (D)Leu, (D)NMeTyr, (D)Pro, (D)Tyr, substituted Gly, MeLeu, MeNLe, Pro, Paf, 4-di-fluoro-Pro, Sarc, or Tyr.

[00253] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Fonnula (Z’) to (Z’-K) wherein X15 is (D)His, substituted His, 2Pai, 3Pal, 4Pal, 4TriazolAla, or 5Pyal; and X16 is absent, (D)NMeTyr or Sarc.

[00254] In certain embodiments, the peptide inhibitor îs the peptide inhibitor of Formula (Z’) to (Z’-K) wherein X15 is (3-Me)His or 3Pal; and X16 is absent or Sarc.

[00255] In certain embodiments, the peptide inhibitor comprises the structure of Formula (Z’): Ac-Pen-Asn-Thr-[W(7-Me)]-Lys(Ac)-Pen-[F(4-2ae)]-[2-Nal]-THP-Glu-Asn-[3-Pal]-XI6-NH₂ (Z’-L) (SEQ ID NO:521) wherein F(4-2-ae) is Phe[4-(2-aminoethoxy)], and the peptide inhibitor is cyciized via a Pen-Pen disulfide bond.

[00256] In certain embodiments, the peptide inhibitor comprises the structure of Formula (Z’): Ac-Pen-Asn-Thr-[W(7-Me)]-Lys(Ac)-Pen-[F(4-2ae)]-[2-Nal]-THP-Glu-Asn-X 15-Sarc-NH₂ (Z’M) (SEQ ID NO:522) wherein F(4-2-ae) is Phe[4-(2-aminoethoxy)], and the peptide inhibitor is cyciized via a Pen-Pen disulfide bond.

[00257] In certain embodiments, the peptide inhibitor is the peptide inhibitor of Formula (Z’) to (Z’-K) wherein XI5 is 3Pal; and X16 is Sarc.

[00258] In certain aspect, the présent invention provides a peptide inhibitor of an interleukin-23 receptor, wherein the peptide inhibitor comprises or is any one of the amino acid sequence set forth in any of Table El A and Table E1B; or a pharmaceutically acceptable sait thereof. In certain aspect, the présent invention provides a peptide inhibitor of an interleukin-23 receptor, wherein the peptide inhibitor comprises or is any one of the amino acid sequence set forth in any of Table El ; or a pharmaceutically acceptable sait thereof.

[00259] In certain aspect, the présent invention provides a peptide inhibitor of an interleukin-23 receptor, wherein the peptide inhibitor comprises or is any one of the amino acid sequence listed below; or a pharmaceutically acceptable sait thereof:

Ac-[(D)Argj-[Abu]-Q-T-[W(7-Ph)]-[Lys(Ac)]-[Cys]-Phe[4-(2-ammoethoxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-dK-[Sarc]-NH₂(SEQ ID NO:1);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[a-MeLys][Lys(Ac)]-N-[(D)Leu)]-[Sarc]-NH₂(SEQ ID NO:2);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[THP]-E-N[(D)Lys]-[Sarc]-NH₂(SEQ ID NO:3);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-ammoethoxy)]-[3-Quin]-[a-MeLys][Lys(Ac)]-N-[(D)His]-[Sarc]-NH₂(SEQ ID NO:4);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂(SEQ ID NO:5);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[THP]-E-N[(D)Leu)]-[Sarc]-NH₂(SEQ ID NO:6);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[a-MeLys][Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂(SEQ ID NO:7);

Ac-[(D)Arg]-[Abu]-Q-T-W-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-N[(D)NMeTyr]-NH₂(SEQ ID NO:8);

Ac-[(D)Arg]-|Pen]-Q-T-W-Q-[Pen]-Phe[4-(2-aminoethoxy )]-[2 -Nal]-[THP]-E-N-N[(D)NMeTyr|-NH₂(SEQ ID NO:9);

Ac-[(D)Arg]-[Pen]-Q-T-W-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[aMeGlu]-N-F[(D)NMeTyr]-NH₂(SEQ IDNO:10);

Ac-[Pen]-N-T-[W(7-Ph)HLys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-E-N[(D)Lys]-[Sarc]-NH₂ (SEQ ID NO: 11 );

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[a-MeLys][Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂ (SEQ ID NO: 12);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-E-N[(D)Leu]-[Sarc]-NH₂ (SEQ ID NO: 13);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-amÎnoethoxy)]-[3Quin]-[a-MeLys][Lys(Ac)]-N-[(D)Leu]-[Sarc]-NH2 (SEQ ID NO;l4);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-E-N-H[Sarc]-NH₂ (SEQ ID NO:I5);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[a’MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:l6);

Ac-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂ (SEQ ID NO: 17);

Ac-[Abu]-Q-T-[W(7-Ph)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂ (SEQ ID NO: 18);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Leu]-[Sarc]-NH₂ (SEQ ID NOS:20, 25);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-arninoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂ (SEQ ID NO:21);

Ac-[Pen]-N-T-[W(7-Me)HLys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂ (SEQ ID NO:22);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:23);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[(D)Leu]-[Sarc]-NH₂ (SEQ ID NO:24);

Ac-[Pen]-N-T-[W(7-Me)j-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Leu]-[Sarc]-NH₂ (SEQ ID NO:25);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-amînoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂ (SEQ ID NO:26);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nai]-[a-MeLys][Lys(Ac)]-N-H-[Sarcl-NH₂ (SEQ ID NO:27);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[(D)Leu]-[Sarc]-NH₂ (SEQ ID NO:28);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Leu]-[Sarc]-NH₂ (SEQ ID NO:29);

Ac-[Pen]-N-T-[W(7-M.e)]-[Lys(bAla)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal}-[THP]-E-N-H[Sarc]-NH₂ (SEQ ID NO:30);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(bAla)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:31);

Ac-[Pen]-N-T-[W(7-Et)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂ (SEQ (D NO:32);

Ac-[Pen]-N-T-[W(7-Et)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:33);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-Et)]-[a-MeLys^ (Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:34);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)HPen]-Phe[4-(2-aminoethoxy)HW(4-Me)]-(a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:35);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(6-Me)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:36);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4~(2-aminoethoxy)]-[W(4-OMe)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:37);

Ac-[Pen]-N-T-(W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-i-Pr)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:38);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-amînoethoxy)]-[W(7-nPr)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc|-NH₂ (SEQ ID NO:39);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-OMe)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:40);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(6-Cl)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:41);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(5-OMe)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:42);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(3-MePh)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:43);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)HW(6-Ph)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:44);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aininoethoxy)]-[W(6-Et)]-|a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO;45);

Ac-[Pen]-N-T-[W(7-(2-FPh)]- [Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:46);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Leu]-[(D)NMeTyrJ-NH₂ (SEQ ID NO:47);

Ac-[Pen]-N-T-[W(7-Me)HLys(Ac)]-[Pen]-Phe[4-(2~aminoethoxy)]-[2-Nai]-[a-MeLys][Lys(Ac)]-N-[(D)Lys]-[(D)NMeTyr]-NH₂ (SEQ ID NO:48);

Ac-[Pen]-N-T-[W(7-(2-OMePh)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:49);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-Ph)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:50);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nai]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:51 );

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂ (SEQ ID NO:52);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-E-N-H[Sarc]-NH₂ (SEQ IDNO:53);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-S-H[Sarc]-NH₂ (SEQ ID NO:54);

Ac-[Pen]-S-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂ (SEQ 1DNO:55);

Ac-[Pen]-S-T-[W(7-Me)]-[Lys( Ac)]-[Pen]-Phe [4-(2-aminoethoxy )]-[2-Nal]-[THP]-E-S-H[Sarc]-NH₂ (SEQ ID NO:56);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[(D)NMeTyr]-NH₂ (SEQ ID NO:57);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-F-((D)NMeTyr]-NH₂ (SEQ ID NO:58);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-S-H[Sarc]-NH₂ (SEQ ID NO:59);

Ac-[Pen]-S-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂ (SEQ ID NO:60);

Ac-[Pen]-S-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-S-H[Sarc]-NH₂ (SEQ ID NO:6l);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-NalHTHP]-E-N-H[(D)NMeTyr]-NH₂ (SEQ IDNO:62);

F ⁷⁶

Ac-[Pen]-N-T-[W(7-Me)HLys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-[(D)Asn]H-(Sarc]-NH₂ (SEQ ID NO:63);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-G-H[Sarc]-NH₂ (SEQ ID NO:64);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-[h(Ser)]H-[Sarc]-NH₂ (SEQ ID NO:65);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H-PNH₂ (SEQ ID NO:66);

Ac-[Pen]-N-T-[W(7-(2-Nal))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H10 [Sarc]-NH₂ (SEQ ID NO:67);

Ac-[Pen]-N-T-[W(7-3BiPh)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂ (SEQ IDNO:68);

Ac-[Pen]-N-T-[W(7-(Phenanthren-5-yl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-amÎnoethoxy)]-[2-Nal][THP]-E-N-H-[Sarc]-NH₂ (SEQ ID NO:69);

Ac-[Pen]-N-T-[W(7-(4-Anthracen-5-yl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-H-[Sarc]-NH₂ (SEQ ID NO;70);

Ac-[Pen]-N-T-[W(7-(l-Nal))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂ (SEQ ID NO:7l);

Ac-[Pen]-N-T-[W(7-(4BiPh))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H20 [Sarc]-NH₂ (SEQ ID NO:72);

Ac-[Pen]-N-T-[W(7-(3,5-t-Bu-Ph))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-H-[Sarc]-NH₂ (SEQ ID NO:73);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[THP]-E-N-H-[Sarc]-NH₂ (SEQ ID NO:74);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-OMe)]-[2-Nal]-[THP]-E-N-H-[Sarc]-NH₂ (SEQ IDNO:75);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[a-MeLys][Lys(Ac)]-N-[2Pal]-NH₂ (SEQ ID NO:78);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]30 [Lys(Ac)]-N-[2Pal]-NH₂ (SEQ ID NO:79);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLysp [Lys(Ac)]-N-[3Pal]-NH₂ (SEQ ID NO:80);

Ac-[PenJ-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-amÎnoethoxy)]-[2-Nal]'[THP]-[Lys(Ac)]N-H-[Sarc]-NH₂ (SEQ ID NO:8l);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-[(D)NMeTyr]-NH₂ (SEQ ID NO:82);

Ac-[(D)Ar_g]-[Pen]-N-T-[W(7-Me)HLys(Ac)HPen]-Phe[4-(2-amino^

MeLys]-E-N-H-((D)NMeTyr]-NH₂ (SEQ ID NO:83);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-Phe[4-aminomethyl]-[(D)NMeTyr]-NH₂ (SEQ ID NO:84);

Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeuHLys(Ac)]-N[(D)His]-NH₂ (SEQ ID NO:85);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)His]-NH₂ (SEQ ID NO:86);

Ac-[(D)ArgHPen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(D)His]-[(D)NMeTyr]-NH₂ (SEQ ID NO:87);

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)HPen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-N-[(D)NMeTyr]-NH₂ (SEQ ID NO:88);

Ac-[Pen]-N-T-[W(7-Me)]ftLys(Ac)]-[PenJ-Phe[4-(2-aminoethoxy)]-[2-Nai]-[a-MeLys][Lys(Ac)]-N-N-[(D)NMeTyr]-NH₂ (SEQ ID NO:89);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Val]-[(D)NMeTyr]-NH₂ (SEQ ID NO:90);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Thr]-[(D)NMeTyr]-NH₂ (SEQ ID N0:9l);

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-(Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(D)His]-NH₂(SEQ ID NO:92);

Ac-[Abu]-N-T-[W(7-Pli)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[3Quîn]-[THP]-E-N-H-[Sarc]-NH2 (SEQ IDNO:93);

Ac-[Abu]-N-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-E-N-H-[Sarc]-NH₂ (SEQ ID NO:94);

Ac-[Abu]-N-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-H[Sarc]-NH₂ (SEQ ID NO:95);

Ac-[Abu]-N-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H-[Sarc]-NH₂ (SEQ IDNO:96);

P 78

Ac-[Abu]-N-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-arninoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:97);

Ac-[Abu]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂ (SEQ ID NO:98);

Ac-[Abu]-N-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂ (SEQ ID NO:99);

Ac-[(D)ArgHAbu]-S-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-NalHTHP]-E-N-H[Sarc]-NH₂ (SEQ ID NO: 100);

Ac-[(D)Arg]-[Abu]-N-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N10 [(D)Leu]-[Sarc]-NH₂ (SEQ IDNO:10I);

Ac-[(D)Arg]-[Abu]-N-T-[W(7-Me)]-[CÎt]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂ (SEQ ID NO:102);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO: 103);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ ID NO: 104);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO: 105);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]20 [Sarc]-NH₂ (SEQ ID NO: 106);

Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ ID NO:107);

Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3PalHSarclNH₂ (SEQ ID NO:108);

Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH₂ (SEQ ID NO: 109);

Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂ (SEQ ID NO:110);

Ac-[Abu]-Q-T-[W(7-Me)HCit]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]30 [Sarc]-NH₂ (SEQ ID NO: III);

Ac-[Abu]-Q-T-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:112);

Ac-[Abu]-Q“T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[bA]NH₂ (SEQ ID NO: 113);

Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-S-[3Pal]-[bA]NH₂ (SEQ ID NO: 114);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-|Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Tl·IP]-E-N-[4Pal][Sarc]-NH₂ (SEQ ID NO:115);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][bA]-NH₂ (SEQ ID NO: 116);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂ (SEQ ID NO:117);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Quin]-[Sarc]-NH₂ (SEQ ID NO: 118);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[ 7Aza-tryptophan]-[Sarc]-NH₂ (SEQ ID NO: 119);

Ac-(Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-[(D)NMeTyr]-NH₂ (SEQ ID NO:120);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][(D)NMeTyrj-NH₂ (SEQ IDNO:121);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-[(D)NMeTyr]-NH₂ (SEQ ID NO: 122);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)|-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][(D)NMeTyr]-NH₂ (SEQ ID NO:I23);

Ac-[Pen]-S-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-S-[3Pal][Sarc]-NH₂ (SEQ ID NO:124);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]'[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-S-[3Pal][Sarc]-NH₂ (SEQ ID NO:125);

Ac-[Pen]-N-T-[W(7-Ph)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[SarcjNH₂ (SEQ IDNO:I26);

Ac-[Pen]-N-T-[W(7-Ph)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH₂ (SEQ ID NO:127);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3PaI]-[bA]-NH2 (SEQ IDNO:130);

) 80

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][bA]-NH₂ (SEQ ID NO:131);

Ac-[Pen]-S-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-amÎnoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ IDNO:132);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]N-[3Pal]-[Sarc]-NH₂ (SEQ ID NOs:l33, 141);

Ac-[Abu]-Q-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-amînoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH₂ (SEQ ID NO: 134);

Ac-[Abu]-Q-T-[W(7-Ph)]-Q'[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N10 [3Pal]-[Sarc]-NH₂ (SEQ ID NO:135);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂ (SEQ IDNO:136);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aceylaminoethoxy)]-[2-NalHTHP][Lys(Ac)]-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:137);

Ac-[Pen]-E-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-amînoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO: 138);

Ac-[Pen]-E-T-[W(7-Ph)HLys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂ (SEQ IDNO:139);

Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]20 NH₂ (SEQ ID NO: 140);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]N-[3Pal]-[Sarc]-NH₂ (SEQ IDNO:141);

Ac-[Pen]-N-T-[W(7-(3-carboxamidophenyl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO: 142);

Ac-[Pen]-N-T-[W(7-pyrimidin-5-yl)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]E-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO: 143);

Ac-[Pen]-N-T-[W(7-imidazopyridinyl)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQ IDNO:144);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[NMe(Lys)]30 [Lys(Ac)]-N-[His_3Me]-NH₂ (SEQ ID NO:145);

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)HLys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[His_3Me]-NH₂ (SEQ ID NO: 146);

Ac-[ren]-N-T-[W(7-(4Quin))J-[Lys(Ac)]-[Pen]-rhe[4-(2-aminoethoxy)]-[2-Nal]-[THP]'E-N[3Pal]-[Sarc]-NH₂ (SEQ ID NO:147);

Ac-[Pen]-N-T-[(W(7-(3-pyrazol-l-yl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQIDNO:148 151);

Ac-[Pen]-N-T-[(W(7-(5-Et))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nai]-[THP]-E-N[3Pal]-[Sarc]-NH₂ (SEQ IDNO:I49);

Ac-[Pen]-N-T-[W(5-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ ID NO: 150);

Ac-[Pen]-N-T-[(W(7-(3-pyrazoM-yl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-(2-Nal][THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:151);

Ac-[Pen]-N-T-[W(7-indazol-5-yl)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[TI-lP]-EN-[3Pal]-[Sarc]-NH₂ (SEQ ID NO: 152);

Ac-[Pen]-N-T-[W(4-F)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ ID NO: 153);

Ac-[Pen]-N-T-[W(5-CN)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ IDNO:154);

Ac-[Pen]-N-T-[W(7-CN)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ IDNO:I55);

Ac-[Pen]-N-T-[W(4-OMe)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Pal]-[Sarc]-NH₂ (SEQ IDNO:156);

Ac-[Pen]-N-T-[W(4-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ IDNO:157);

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH₂ (SEQ ID NOs: 158, 162, 284);

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-E-N-[3Pal]-[Sarc]NH₂ (SEQ ID NO: 159, 285);

Ac-[Pen]-N-T-[W(5-Ca)]-[Lys(Ac)]-[Pen]-Phe[4-(2-amÎnoethoxy)]-[2-Nal]-[THPj-E-N-[3Pal][Sarc]-NH₂ (SEQ IDNO:160);

AC[Pen]-N-T-[Trp_4Aza]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ ID NO:161);

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]’[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH₂ (SEQ ID NO: 162);

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal][Sarc]-NH₂ (SEQ IDNO:163);

Ac-[(D)ArgHPen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)H2-Nal]-[THP]-EN-[(5Pyal)]-NH₂ (SEQ ID NO:164);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-amÎnoethoxy)]-[2-NaI]-[a-Me-Lys](Lys(Ac)]-N-[(5Pyal)]-NH₂ (SEQ ID NO: 165);

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(l-Me)His]-NH2 (SEQ ID NO: 166);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys][Lys(Ac)]-N-| (l-Me)His]-NH₂ (SEQ ID NO: 167); or

Ac-[Pen]-N -T-[W(7-Me]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-Me-Lys][Lys(Ac)]-N-[3Pal]-[(D)NMeTyr]-NH2 (SEQ ID NO: 168);

and wherein the peptide inhibitor is cyciized via a Pen-Pen disulfide bond; or via an Abu-C thîoether bond;

or a pharmaceutically acceptable sait thereof.

[00260] In certain aspect, the présent invention provides a peptide which comprises or is:

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-NH₂ (SEQ ID NO:80);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Pa!]-[Sarc]-NH₂ (SEQ ID NO:104);

Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ ID NO: 108);

Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3PaI]-[Sarc]-NH₂ (SEQ ID NO:110);

Ac-[Abu]-Q-T-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:112);

Ac-[Pen]-N-T-[W(7-Me)HLys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Quin]-[Sarc]-NH₂ (SEQ ID NO: 118);

Ac-[Pen]-S-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-NaI]-[THP]-E-S[3Pal]-[Sarc]-NH₂ (SEQ ID NO: 124); or

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-amînoethoxy)]-[2-Nal]-[THP]-E-S[3Pal]-[Sarc]-NH₂ (SEQ ID NO: 125);

and wherein the peptide inhibitor is cyclized via a Pen-Pen disulfîde bond; or via an Abu-Cys thioether bond;

or a pharmaceutically acceptable sait thereof.

[00261] In certain aspect, the présent invention provides a peptide which comprises or is:

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-ammoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-[Sarc]-NH₂ (SEQ IDNO:105);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen|-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ IDNO:106);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)H2-Nal]-[THP]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂ (SEQ ID NO:117);

Ac-[Pen]-N-T-[W(7-Ph)]-[Cît]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH₂ (SEQ ID NO;126);

Ac-[Pen]-N-T-[W(7-Ph)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH₂ (SEQ IDNO:127);

Ac-[Abu]-Q-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH₂ (SEQ ID NO:134);

Ac-[Abu]-Q-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂ (SEQ IDNO:135);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂ (SEQ ID NO: 136);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aceylaminoethoxy)]-[2-Nal]-[THP][Lys(Ac)]-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO: 137); or

Ac-[Pen]-E-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy )]-[2-Nal]-[THP]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂ (SEQ IDNO:139);

and wherein the peptide inhibitor is cyclized via a Pen-Pen disulfîde bond; or via an Abu-C thioether bond;

or a pharmaceutically acceptable sait thereof.

[00262Jln certain embodiments, the peptide inhibitor comprises or is any one of the amino acid sequence listed below:

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-EN-[(D)Lys]-[(D)NMeTyr]-NH₂ (SEQ ID NO:201),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-EN-[(D)His]-[(D)NMeTyr]-NH₂ (SEQ IDNO:202),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2~aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Orn]-[(D)NMeTyr]-NH₂ (SEQ ID NO:203),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-((D)Ser]-[(D)NMeTyr|-NH₂ (SEQ ID NO:204),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Phe]-[(D)NMeTyr]-NH₂ (SEQ ID NO:205),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-H-[(D)Tyr]-NH₂ (SEQ ID NO:206),

Ac-[Pen]-N-T-[W(7-Me)]-[(D)Tyr]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]~ [Lys(Ac)]-N-[(D)Lys]-[(D)NMeTyr]-NH₂ (SEQ IDNO:207),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-H-P-NH2 (SEQ ID NO:208),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-H-[(D)Pro]-NH₂ (SEQ IDNO;209),

Ac-[Pen]-N-T-[W(7-Me)]-[Phe(4-CONH2)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Lys]-[(D)NMeTyr]-NH₂ (SEQ ID NO:210),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Na]]-[Acvc]-E-N(D)Phe[4-NH₂]-[Sarc]-NH₂ (SEQ ID NO:211),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-H-NHs (SEQ ID NO:212),

Ac-[Pen]-N-T-[W(7-Me)J-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-N(H)Me (SEQ ID NO:213),

Ac-[Pen]-N-T-[W(7-Me)]-[Phe(4-NH(Ac))]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Lys]-[(D)NMeTyr]-NH₂ (SEQ ID NO:214),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Tyr]-[(D)NMeTyr]-NH₂ (SEQ ID NO:215),

Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac)]-N[(D)Lys]-[(D)NMeTyr]-NH₂ (SEQ ID NO:216),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)H2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)His]-[(D)NMeTyr]-NH₂ (SEQ ID NO:2I7),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[bAla]-[(D)NMeTyr]-NH₂ (SEQ IDNO:218),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-arninoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[bAla]-[(D)NMeTyr]-NH₂ (SEQ ID NO:219),

Ac-[Pen]“N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[bAla]-[(D)NMeTyr]-NH2 (SEQ ID NO:220),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-E-N-H-N(H)Me (SEQ ID NO:221),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[THP]-P-NH₂ (SEQ ID NO:222),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-'Nal]-[THP]-EN-[THP]-[(D)Pro]-NH₂ (SEQ IDNO:223),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[bAla]-[Sarc]-NH₂ (SEQ ID NO:224),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-|Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[(D)Val]-[Sarc]-NH₂ (SEQ ID NO:225),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[(D)Arg]-[Sarc]-NH₂ (SEQ ID NO:226),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[Hph]-[Sarc]-NH₂ (SEQ ID NO:227),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-E-N-Phe[4NH₂]-[Sarc]-NH₂ (SEQ ID NO:228),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-Phe[4-NH₂]-[Sarc]-NH₂ (SEQ ID NO:229),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe(4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-F-[Sarc]-NH₂ (SEQ ID NO:230),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[THP]-[Sarc]-NH₂ (SEQ ID NO:231),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[(D)Leu]-[Sarc]-NH₂ (SEQ IDNO:232),

Ac-[(D)Arg]-[Cys]-N-T-[W(7-Mc)]-[Lys(Ac)]-[aMeCys]-Phe[4-(2-aminoethoxy)]-[2-Nal][Acvc]-E-N-H-[Sarc]-NH₂ (SEQ IDNO:233),

Ac-[(D)Arg]-[Cys]-N-T-[W(7-Me)]-[Lys(Ac)]-[aMeCys]-Phe[4-(2-aminoethoxy)]-[2-Nal][Acvc]-E-N-[(D)Leu]-[Sarc]-NH₂ (SEQ IDNO:234),

Ac’[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:235),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aniinoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[bAla]-[Sarc]-NH₂ (SEQ ID NO:236),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Val]-[Sarc]-NH₂ (SEQ ID NO:237),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Arg]-[Sarc]-NH₂ (SEQ ID NO:238),

Ac-[Pen]-N-T-[W(7-Me)HLys(Ac)]-[Pen]-Phe[4-(2-aniinoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[Hph]-[Sarc]-NH₂ (SEQ ID NO:239),

Ac-[Pen[-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Tyr]-(Sarc]-NH₂ (SEQ ID NO:240),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Tyr]-[Sarc]-NH₂ (SEQ JD NO:24i),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]“[THP]-EN-[4Pal]-NH₂ (SEQ ID NO:242),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[Phe(4-CF3)]-[Sarc]-NH₂ (SEQ ID NO:243),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-Tyr_CHF2-[Sarc]-NH₂ (SEQ ID NO:244),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[THP]-P-NH₂ (SEQ ID NO:245),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-[(D)NMeTyr]-NH₂ (SEQ ID NO:246),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:247),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)HPen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP}-EN-[4Pal]-[Sarc]-NH₂ (SEQ ID NO:248),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Penj-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[Phe(2-aminomethyl)]-[Sarc]-NH₃ (SEQ ID NO:249),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Pro(4,4diF)]-NH₂ (SEQ ID NO:250),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)|-[Pen]-Phe{4-(2-aminoethoxy)J-[2-Nal]-[THP]-EN-[3Pal]-[aMePro]-NH₂ (SEQ ID NO:251),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Aib]-NH₂ (SEQ ÏDNO:252),

Ac-[Pen]-N-T-[W(7-Me)]'[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[His(3-Me)]-[Sarc]-NH₂ (SEQ ID NO:253),

Ac4(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)HPen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[His(3-Me)]-[Sarc]-NH₂ (SEQ ID NO:261 ),

Ac-[(D)Arg]-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[His(3-Me)]-[Sarc]-NH₂ (SEQ ID NO:262),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH₂ (SEQ IDNO:266),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-N(H)Me (SEQ ID NO:267),

[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Pal]-[Sarc]-NH₂ (SEQ ID NO:270),

Ac-[(D)Arg]-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Na]]-[THP]-E-N[3Pal]-[Sarc]-NH₂ (SEQ IDNO:271),

Pr-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-(N-propionylamino)ethoxy)]-[2Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:272),

A c-[(D) Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-(N-(4-hydroxy-3-methyl phenyl) propionylamino) ethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:273),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal(5-Me)]-[Sarc]-NH₂ (SEQ ID NO:276),

Ac4(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)HPen]-Phe[4-(2-aminoethoxy)]-[2-Na]]-[THP]-EN-[3Pal(5-NH₂)]-[Sarc]-NH₂ (SEQ ID NO:277),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[His(3Me)]-N(H)Me (SEQ ID NO:278),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-(2-Nal]-[THP]-EN-[3Pal]-[(D)NMeTyr]-NH₂ (SEQ ID NO:279),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-(Lys(Ac)]-[Pen]-Phe[4-(2-amînoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Gly(N-cyclohexyImethyl)]-NH₂ (SEQ IDNO:280),

Ac-[(D)ArgJ-[Pen]-N-T-LW(7-Me)]-[Lys(Ac)J-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3PaJ]-[GJy(N-isobutyl)]-NH2 (SEQ ID NO:281),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal(3-Me)]-NH₂ (SEQ IDNO:282),

Ac-[(D)Arg]-[aMeCys]-N-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[3Pal|-[Sarc]-NH₂ (SEQ ID NO:283),

Ac-[Pen]’N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NHî (SEQ ID NO:284),

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-NaI]-[Acvc]-E-N-[3Pal]-[Sarc]NH₂ (SEQ ID NO:159,285),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH₂ (SEQ ID NO:286),

Ac-[Pen]-[Gly(Allyl)]-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Tyr(O-Allyl)]-[2-Nal]-[THP]-[Lys(Ac)]N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:287),

Ac-[Pen]-[Gly(AlIyl)]-D-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Tyr(O-Allyl)]-[2-Nal]-[THP]-[Lys(Ac)]N-[3Pal]-[Sarc]-NH₂(SEQ ID NO:288),

Ac-[Pen]-[Gly(Allyl)]-T-(W(4-F)]-[Lys(Ac)]-[Pen]-[Tyr(O-Allyl)]-[2-Nal]-[THP]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂ (SEQ ID NO:289),

Ac-[Pen]-N-D-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ 1DNO:290),

Ac-lPen]-L-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)H2-Nal]-[THP]-E-N-[3Pal][SarcJ-NHz (SEQ IDNO:291),

Ac-[Pen]-N-T-[W(7-Me)HLys(Ac)]-[Pen]-[Phe(4-CONH2)H2-Nal]-[a-MeLys]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂ (SEQ ID NO:299),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-F-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO:308),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[(D)Tyr]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]NH₂ (SEQ ID NO:309),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-OMe)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pa [Sarc]-NH₂ (SEQ IDNO:3IO),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[THP]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂ (SEQ ID NO:311),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(N-acetyl-N-propyl)]-[Pen]-Phe[4-(2-aminoethoxy)J-[2-Nal][THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:332), Ac-[Pen]-N-T-[W(7-Me)]-[Lys(N-acetyl-N-butyl)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:333), Ac-[Pen]-N-T-[W(7-Me)]-[Lys(N-acetyl-N-isobutyl)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:334), Ac-[Pen|-N-T-[W(7-Me)]-[Lys(N-acetyl-N-benzyl)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:335), Ac-[Pen]-L-T-[W(7-Me)]-[Lys(Ac)|-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[aMeLeu]-E-N-[3Pal][Sarc]-NH₂ (SEQ ID NO:339), Ac-[Pen]-L-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-OMe)]-[2-Nal]-[aMeLeu]-E-N-[3Pal]-[Sarc]NH₂ (SEQ ID NO:347), or

Ac-[Abu]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ ID NO:373), and wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or via an Abu-C thioether bond;

or a pharmaceutically acceptable sait thereof.

[00263] In certain embodiments, the peptide is

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ 1DNO:104),

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ ID NO: 106),

Ac- [Pen]-N-T-W-[Ly s(Ac)]-[Pen] -Phe [4-(2-aminoethoxy)] -[2-Nal ]-[THP]-E-N-[3 Pal] -[Sarc] NH₂ (SEQ IDNOs:158, 162,284),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH₂ (SEQ ID NOs:247, 266), Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[His(3-Me)]-[Sarc]-NEI₂ (SEQ IDNO:261), or

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-N(H)Me (SEQ ID NO:267), wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or a pharmaceutically acceptable sait thereof.

[00264] In certain embodiments, the peptide is

Ac-[Penl-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-NaI]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ IDNO:I04), wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or a pharmaceutically acceptable sait thereof.

[00265] In certain embodiments, the peptide is

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ IDNO:l06), wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or a pharmaceutically acceptable sait thereof.

[00266] In certain embodiments, the peptide is

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NEh (SEQ ÏD NOs:l 58, 162,248), wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or a pharmaceutically acceptable sait thereof.

[00267] In certain embodiments, the peptide is

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH₂ (SEQ ID NOs:247, 266), wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or a pharmaceutically acceptable sait thereof.

[00268] in certain embodiments, the peptide îs

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[His(3-Me)]-[Sarc]-NH₂ (SEQ IDNO:261), wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or a pharmaceutically acceptable sait thereof.

[00269] In certain embodiments, the peptide îs

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-amînoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-N(H)Me (SEQ ID NO:267), wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond, or a pharmaceutically acceptable sait thereof.

[00270] In certain embodiments, the peptide is

[N3_Acid]-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:274), or

[FPrpTriazoleMe_Acid]-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:275), wherein the peptide inhibitor is cyclized via a Pen-Pen disulfïde bond, or a pharmaceutically acceptable sait thereof.

[Û0271]In certain embodiments, XI5 is Arg, (D)Arg, aMeArg, His, (D)His, Sar, 2-Pal, or 3-Pal; wherein 2-Pal is 2-pyridyl substituted alanine, and 3-Pal is 3-pyridyl substituted alanine:

Ο

OH nh₂ ² (2-Pal) or

Ο

OH ^NH2 (3-Pal).

[00272]In certain embodiments, XI1 is 3-Quin, and wherein 3-Quin is Ph of Phe is replaced with 3-quinolinyl or is NH-C(3-quinolinylmethyl)(H)-C(O)- or:

[00273] In certain aspect, the present invention provides a peptide inhibitor of an interleukin23 receptor, wherein the peptide inhibitor comprises or is any one of the amino acid sequence listed below; or a pharmaceutically acceptable sait thereof:

[00274] In certain embodiments, the peptide is, or a pharmaceutically acceptable sait thereof:

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]5 [Lys(Ac)]-N-[3Pal]-NH₂; (SEQ ID NO:80)

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-[Sarc]-NH₂; (SEQ ID NO: 103)

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N5 [3Pal]-[Sarc]-NH₂; (SEQ ID NO: 104)

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Pal]-[Sarc]-NH₂; (SEQ ID NO: 106)

Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]5 [Sarc]-NH₂; (SEQ ID NO: 107)

Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂; (SEQ ID NO: 108)

Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]

[Sarc]-NH₂; (SEQ ID NO:109)

Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]N-[3Pal]-[Sarc]-NH₂; (SEQ ID NO:l 10)

Ac-[Abu]-Q-T-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂; (SEQ ID NO; III)

Ac-[Abu]-Q-T-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-aminoethûxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-[Sarc]-NH₂; (SEQ ID NO: 112)

Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-an)inoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][bA]-NH₂; (SEQ ID NO: 113)

Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-S-[3Pal][bA]-NH₂; (SEQ ID NO: 114)

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N5 [3Pal]-[bA]-NH₂ (SEQ ID NO: 116)

Ac- [PenJ-N-T- [ W(7-Ph)] - [ Ly s(Ac)J- [Pen] -Phe [4-(2-am i noethoxy)] - [2-Nal] -[THP][Lys(Ac)]-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:117)

100

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Quin]-[Sarc]-NH₂; (SEQ ID NO: 118)

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N5 [3Pal]-[(D)NMeTyr]-NH₂ (SEQ ID NO:121)

ΙΟΙ

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Pal]-[(D)NMeTyr]-NH₂ (SEQ ID NO:l23)

Ac-[Pen]-S-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-S5 [3Pal]-[Sarc]-NH₂; (SEQ ID NO:124)

νη₂

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-S[3Pal]-[Sarc]-NH₂; (SEQ IDNO:125)

Ac-[Pen]-N-T-[W(7-Ph)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]5 [Sarc|-NH₂ (SEQ ID NO:127)

103

Ac-[Abu]-Q-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ ID ΝΟΩ34)

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]5 [Lys(Ac)]-N-[3Pal]-[Sarc]-NH₂ (SEQ IDNO:136)

O

104

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMe(Lys)][Lys(Ac)]-N-[His_3Me]-NH₂; (SEQ IDNO:l45)

Ac-[Pen]-N-T-[W(7-(4Quin))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E

N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:l47)

105

Ac-[Pen]-N-T-[(W(7-(3-pyrazol-l-yl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[3Pal]-[Sarc]-NH2 (SEQ IDNO:l48)

106

Ac-[Pen]-N-T-[(W(7'(5-Et-Ph))]-[Lys(Ac)]-[Pen]-Phe[4-(2-amînoethoxy)]-[2-Nal]-[THP]E-N-[3Pa!]-[Sarc]-NH₂ (SEQ ID NO:I49)

Ac-[Pen]-N-T-lW(4-F)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-NaI]-[THP]-E-N5 [3Pal]-[Sarc]-NH₂ (SEQ ID NO: 153)

107

Ac-[Pen]-N-T-[W(7-CN)]-[Lys(Ac)]-[Pen]-PheI4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Pal]-[Sarc]-NH₂ (SEQ ID NO:155)

Ac-[Pen]-N-T-[W(4-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N

[3Pal]-[Sarc]-NH₂ (SEQ ID NO: 157)

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-amînoethoxy)]-[2-Nal]-|THP]-E-N-[3Pal][Sarc]-NH2 (SEQ ID NO: 158)

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-amînoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]5 [Sarc]-NH₂ (SEQ ID NO: 162)

109

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[THP]-E-N-[3Pal]5 [Sarc]-NH₂; (SEQ ID NO:286)

I ΙΟ

Ac-[Pen]-[Gly(Allyl)]-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Tyr(O-Allyl)]-[2-Nal]-[THP][Lys(Ac)]-N-[3Pal]-[Sarc]-NH₂; (SEQ ID NO:287)

Ac-[Pen]-N-D-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N5 [3Pal]-[Sarc]-NH₂; (SEQ ID NO:290)

Ac-[Pen]-L-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-amînoethoxy)]-[2-Nal]-[THP]-E-N[3Pal]-[Sarc]-NH₂; (SEQ IDNO:291)

112

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-F-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]NH₂; (SEQ ID NO:308)

113

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)j-[2-Nal]-[THP]-[Lys(Ac)j-N[3Pal]-[Sarc]-NH₂; (SEQ IDNO:311)

Ac-[Pen]-L-T-[W(7-Me)]-[Lys(Ac)]<Pen]-[Phe(4-CONH2)]-[2-Nal]-[aMeLeu]-E-N-[3Pal]-

O

[00275] In certain aspect, the present invention provides a peptide inhibitor of an interleukin23 receptor, wherein the peptide inhibitor comprises or is any one ofthe amino acid sequence listed below; or a pharmaceutically acceptable sait thereof:

114

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-arninoethoxy)]-[2-Nal][THP]-E-N-[His(3-Me)]-[SarcJ-NH₂; (SEQ ID NO:26l )

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]

N-[3Pal]-[Sarc]-NH₂; (SEQ ID NO:299)

115

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-OMe)]-[2-Nal]-[THP]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂; (SEQ ID NO:310)

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(N-acetyl-N-propyl)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]5 [THP]-E-N-[3Pal]-[Sarc]-NH₂; (SEQ ID NO:332)

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(N-acetyl-N-butyl)]-[Pen]-Phe[4-(2-aminoethoxy)]-{2-Nal][THP]-E-N-[3Pal]-[SarcJ-NH₂; (SEQ ID NO:333)

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(N-acetyl-N-benzyl)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]5 [THP]-E-N-[3Pal]-[Sarc]-NH₂; (SEQ ID NO:335)

117

Ac-[Pen]-L-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-OMe)]-[2-Nal]-[aMeLeu]-E-N-[3Pal]'

[Sarc]-NH₂; (SEQ ID NO:347)

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-OMe)J-[2-NaJ]-[THP]-L-N-[3Pal]-[Sarc]5 NH₂; (SEQ ID NO:351)

Additional Characteristics of Peptide Inhibitors

[00276] Any of the peptide inhibitors of the présent invention may be further defined, e.g., as described below. It is understood that each of the further defining features described herein may be applied to any peptide inhibitors where the amino acids designated at particular positions allow the presence of the further defining feature. In particular embodiments, these features may be 10 présent in any of the peptides of Formula (I)-(XVIIId).

[00277] In various embodiments, R¹ is a bond, hydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12 aryl C1-C6 alkyl, or a C1-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing, e.g., acetyl. It is understood that the R¹ may replace or be présent in addition to the typical amine group located at the amino terminus of a peptide. It is further understood that 15 R¹ may be absent. In certain embodiments, the peptide inhibitor comprises an N-terminus selected from hydrogen, a C1-C6 alkyl, aC6-C12 aryl, aC6-C12 aryl C1-C6 alkyl, oraCl-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing, e.g., acetyl. In particular embodiments of any of the peptide inhibitors described herein, R¹ or the N-terminal moiety is hydrogen. In certain embodiments, R¹ is a bond, e.g., a covalent bond.

119 (00278] In certain embodiments of any of the peptide inhibitors having any of the various Formulas set forth herein, R¹ or the N-terminal moiety is selected from methyl, acetyl, formyl, benzoyi, trifluoroacetyl, isovaleryl, isobutyryl, octanyl, and the conjugated amides of lauric acid, hexadecanoic acid, and γ-Gki-hexadecanoîc acid. In certain embodiments, R¹ or the N-terminal moiety is pGlu. In certain embodiments, R¹ is hydrogen. In particular embodiments, R¹ îs acetyl, whereby the peptide inhibitor is acylated at its N-terminus, e.g., to cap or protect an N-terminal amino acid residue, e.g., an N-terminal Pen residue.

[00279] In certain embodiments of any of the peptide inhibitors described herein, R¹ or the Nterminal moiety is an acid, In certain embodiments, R¹ or the N-terminal moiety is an acid selected from acetic acid, formic acid, benzoic acid, trifluoroacetic acid, isovaleric acid, isobutyric acid, octanoic acid, lauric acid, hexadecanoic acid, 4-Biphenylacetîc acid, 4-fluorophenylacetic acid, gallic acid, pyroglutamîc acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumarîc acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxy benzoyi) benzoic acid, cinnamic acid, mandelic acid, 4-methylbicyclo(2.2.2)-oct-2-ene-I-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, an alkylsulfonîc acid and an arylsulfonic acid.

[00280] In particular embodiments, R¹ or the N-terminal moiety is an alkylsulfonîc acid selected from methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, and 2hydroxyethanesulfonic acid.

[00281] In particular embodiments, R¹ or the N-terminal moiety is an arylsulfonic acid selected from benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4toluenesulfonic acîd, and camphorsulfonic acid.

Peptide Dimers

[00282] In certain embodiments, the présent invention includes dimers of the monomer peptide inhibitors described herein, including dimers of any of the monomer peptide inhibitors described herein or in the accompanying tables. These dimers fait within the scope of the general term “peptide inhibitors” as used herein. Illustrative dimers of the présent invention are also shown in the accompanying tables, which indicate the dimerized monomer subnits in brackets followed by the linker. Unless otherwise indicated, the subunits are linked via theîr C-termini. The term “dimer,” as in a peptide dimer, refers to compounds in which two peptide monomer subinîts are linked. A peptide dimer inhibitor of the présent invention may comprise two identical monomer

120 subunits, resulting in a homodimer, or two non-identical monomer subunits, resulting in a heterodimer. A cysteine dimer comprises two peptide monomer subunits lînked through a disulfîde bond between a cysteine residue in one monomer subunit and a cysteîne residue in the other monomer subunit.

[00283] In some embodiments, the peptide inhibitors of the présent invention may be active in a dimer conformation, in particular when free cysteine residues are présent in the peptide. In certain embodiments, this occurs either as a synthesized dimer or, in particular, when a free cysteine monomer peptide is présent and under oxidizing conditions, dimerizes. In some embodiments, the dimer is a homodimer. In other embodiments, the dimer is a heterodimer.

[00284] In certain embodiments, monomer subunits of the présent invention may be dimerized by a suitabie linking moiety, e.g., a disulphîde bridge between two cysteine residues, one in each peptide monomer subunit, or by another suitabie linker moiety, includîng but not limited to those defined herein. Some of the monomer subunits are shown having C- and N-termini that both comprise free amine. Thus, to produce a peptide dimer inhibitor, the monomer subunit may be modified to eliminate either the C- or N-terminal free amine, thereby permitting dimerîzation at the remaining free amine. Further, in some instances, a terminal end of one or more monomer subunits îs acylated with an acylating organic compound selected from the group consisting of: Trifluoropentyl, Acetyl, Octonyl, Butyl, Pentyl, Hexyl, Palmityl, Trifluoromethyl butyrîc, cyclopentane carboxylic, cyclopropylacetic, 4-fluorobenzoic, 4-fluorophenyl acetic, 320 Phenylpropionic, tetrahedro-2H-pyran-4carboxylic, succinic acid, and glutaric acid. In some instances, monomer subunits comprise both a free carboxy terminal and a free amino terminal, whereby a user may selectively modify the subunit to achieve dimerization at a desired terminus. One having skill in the art therefore, will appreciate that the monomer subunits of the instant invention may be selectively modified to achieve a single, spécifie amine for a desired 25 dimerization.

[00285] It is further understood that the C-terminal residues of the monomer subunits disclosed herein are optionally amides. Further, it is understood that, in certain embodiments, dimerization at the C-terminus îs facilitated by using a suitabie amino acid with a side chain having amine functionality, as is generally understood in the art. Regarding the N-terminal residues, it is 30 generally understood that dimerization may be achieved through the free amine of the terminal residue, or may be achieved by using a suitabie amîno acid side chain having a free amine, as îs generally understood in the art.

I 121

[00286] The linker moieties connecting monomer subunits may include any structure, length, and/or size that is compatible with the teachings herein. In at least one embodiment, a linker moiety îs selected from the non-limiting group consisting of cysteine, lysine, DIG, PEG4, PEG4-bîotin, PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, IDA, ADA, Boc-IDA, Glutaric acid, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, 1,2phenylenediacetic acid, Triazine, Boc-Triazine, IDA-biotin, PEG4-Biotin, AADA, suitable aliphatics, aromatics, heteroaromatics, and polyethylene glycol based linkers having a molecular weight from approximately 400Da to approximately 40,000Da. In certain embodiments, PEG2 is HO2CCH2CH2OCH2CH2OCH2CH2CO2H. Non-limiting examples of suitable linker moieties are provided in Table 2. ¹

Table 2. Illustrative Linker Moieties

Abbrevatîon	Description	Structure
DIG	DIGlycolic acid,	0 u
PEG4	Bifunctional PEG linker with 4 PolyEthylene Glycol units	0 0
PEG 13	Bifunctional PEG linker with 13 PolyEthylene Glycol units	0 i? 1 λ LO. A .x A 0 v W v 0
PEG25	Bifunctional PEG linker with 25 PolyEthylene Glycol units	0 H 1 - XX L0. A x A 0 0 JaTO - O
PEG1K	Bifunctional PEG linker with PolyEthylene Glycol Mol wt of lOOODa
PEG2K	Bifunctional PEG linker with PolyEthylene Glycol Mol wt of 2000Da
PEG3.4K	Bifunctional PEG linker with PolyEthylene Glycol Mol wt of 3400Da

122

Abbrevation	Description	Structure
PEG5K	Bifunctional PEG linker with PolyEthylene Glycol Mol wt of 5000Da
DIG	DIGlycolic acid	0 o JL JL, O '' 0
β-Ala-IDA	β-Ala-Iminodiacetic acid	0 οθί VL 0=^ 0
Boc-β -AlaIDA	Boc- β -Ala-lminodiacetic acid	y0 0 ^'^0 0
Ac-β -Ala IDA	Ac- β -Ala-lminodiacetic acid	.f° Z O O Je z JL O o
ΙΟΑ-β-AlaPalm	Palmityl- β -Ala-lminodiacetic acid	V t>· É
GTA	Glutaric acid	0 o

123

Abbrevation	Description	Structure
PMA	Pemîlic acid	o 0
AZA	Azelaic acid	O \=O O
DDA	Dodecanedioic acid	0 Â /x Zx ZX x'x z° g x-' γ 0
IPA	Isopthalic aicd	0 o
1,3-PDA	1,3- Phenylenediacetic acid	o γ—/ O P o
1,4-PDA	1,4- Phenylenediacetic acid	o o
1,2-PDA	1,2 - Phenylenediacetic acid	0 0 o 0

124

Abbrevation	Description	Structure
Triazine	Amino propyl Triazine di-acid	O ? A Yf 2» Z z
Boc-Triazîne	I Boc-Triazine di-acid	z. J 1 ΛΛ o O
ADA	Amino diacetic acid (which may also be referred to as Iminodi acetic acid)	0 O JL JL o — o
AADA	n-Acetyl amino acetic acid (which may also be referred to as Nacetyl iminodiacetic acid)	O. 0 Y o
PEG4-Biotin	PEG4-Biotin (Product number 10199, QuantaBioDesign)	V

125

Abbrevation	Description	Structure
IDA-Biotin	N-Biotin- β -Ala-Iminodîacetic acîd	M ? H Y O OH
Lys	Lysine	h2n .. JL .OH h2n o

[00287] In some embodiments, a peptide dimer inhibitor is dimerized via a linker moiety. In some embodiments, a peptide dimer inhibitor is dimerized via an intennolecular disulfide bond formed between two cysteine residues, one in each monomer subunit. In some embodiments, a peptide 5 dimer inhibitor is dimerized via both a linker moiety and an intermolecular disulfide bond formed between two cysteine residues. In some embodiments, the intramolecular bond îs a thîoether, lactam, triazole, selenoether, diselenide or olefin, instead of the disulfide bond.

[00288]One having skill in the art will appreciate that the linker (e.g., C- and N-termînal linker) moieties disclosed herein are non-limitîng examples of suitable linkers, and that the présent invention may include any suitable linker moiety. Thus, some embodiments of the présent invention comprises a homo- or heterodimer peptide inhibitor comprised of two monomer subunits selected from the peptides shown in any of tables herein or comprising or consistîng of a sequence presented in any of tables herein, wherein the C- or N-termini of the respective monomer subunits (or internai amino acid residues) are linked by any suitable linker moiety to provide a dimer peptide inhibitor having 1L-23R inhîbitory activity. In certain embodiments, a linker binds to the N- or Cterminus of one monomer subunit and an internai amino acid residue of the other monomer subunit making up the dimer. In certain embodiments, a linker binds to an internai amino acid residue of one monomer subunit and an internai amino acîd residue of the other monomer subunit making up the dimer. In further embodiments, a linker binds to the N-or C-terminus of both subunits.

126

[00289] In particular embodiments, one or both of the monomer subunits comprise the sequence or structure of any one of Formula (I)-(XVIIId), or shown in Table EJ A, Table El B, or any of the peptides described herein.

[00290] In certain embodiments, a peptide dimer inhibitor has the structure of Formula XII: (R’-X-RVL (XII)

[00291] or a pharmaceutically acceptable sait or solvaté thereof,

[00292] wherein each R¹ is independently absent, a bond (e.g., a covalent bond), or Ri is selected from hydrogen, a C1-C6 alkyl, a C6-CI2 aryl, a C6-C12 aryl C1-C6 alkyl, a C1-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing;

| [00293] each R² is independently absent, a bond (e.g., a covalent bond), or selected from OH or NH₂; L is a linker moiety; andeach X is an independently selected peptide monomer subunit comprising a sequence of Formula (I)-(XVIIId), as described herein. In certain embodiments, one or both peptide monomer subunit of a peptide dimer inhibitor is cyclized, e.g., via an întramolecular bond between X4 and X9. In certain embodiments, one or both peptide monomer subunits is linear or not cyclized.

[00294] In particular embodiments, each R¹ is independently a bond (e.g., a covalent bond), or selected from hydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12 aryl CI-C6 alkyl, a C1-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing. In particular embodîmetns, the N-tenninus of each subunit includes a moiety selected from hydrogen, a CI-C6 alkyl, a C6-C12 aryl, a C6-C12 aryl C1-C6 alkyl, a CI-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing.

[00295] In certain embodiments of any of the peptide inhîbîtors having any of the various Formulae set forth herein, each R¹ (or N-terminal moiety) is selected from methyl, acetyl, formyl, benzoyl, trifluoroacetyl, isovaleryl, isobutyryl, octanyl, and the conjugated amides of lauric acid, hexadecanoic acid, and γ-Glu-hexadecanoic acid.

[00296] In particular embodiments, each R² (or C-terminal moiety) is independently a bond (e.g., a covalent bond), or selected from OH orNH₂.

[00297] In particular embodiments of any of the peptide dimer inhîbîtors described herein, either or both R¹ is hydrogen.

[00298] In particular embodiments of peptide dimer inhîbîtors of the présent invention, the linker moiety (L) is any of the linkers described herein or shown in Table 1 or 7. In certain embodiments, L is a lysine linker, a diethylene glycol linker, an iminodiacetic acid (IDA) linker, a β-Alaiminodiaceticacîd (β-Ala-IDA) linker, or a PEG linker.

127

[00299] In various embodiments of any of the peptide dimer inhibitors, each of the peptide monomer subunits is attached to a linker moiety via its N-terminus, C-terminus, or an internai amino acid residue. In certain embodiments of any of the peptide dimer inhibitors, the N-terminus of each peptide monomer subunit is connected by a linker moîety.In certain embodiments of any of the peptide dimer inhibitors, the C-terminus of each peptide monomer subunit is connected by a linker moiety. In certain embodiments of any of the peptide dimer inhibitors, each peptide monomer subunit is connected by a linker moiety attached to an internai amino acid.

Peptide Inhibitor Conjugales and Biopolymers

[00300] In certain embodiments, peptide inhibitors of the présent invention, including both monomers and dimers, comprise one or more conjugated Chemical substituents, such as lipophilie substituents and polymeric moieties, which may be referred to herein as half-life extension moieties. Without wishing to be bound by any particular theory, it is believed that the lipophilie substituent binds to albumin in the bloodstream, thereby shielding the peptide inhibitor from enzymatic dégradation, and thus enhancing its half-life. In addition, it is believed that polymeric moieties enhance half-life and reduce clearance in the bloodstream.

[00301] In additional embodiments, any of the peptide inhibitors, e.g. peptides of Formula (I)(XVIIId) further comprise a linker moiety attached to an amino acid residue présent in the inhibitor, e.g., a linker moiety may be bound to a side chain of any amino acid of the peptide inhibitor, to the N-terminal amino acid ofthe peptide inhibitor, or to the C-terminal amino acid of the peptide inhibitor.

[00302] In additional embodiments, any of the peptide inhibitors e.g. peptides of Formulas (I)(XIV), further comprise half-life extension moiety attached to an amino acid residue présent in the inhibitor, e.g., a half-life extension moiety may be bound to a side chain of any amino acid of the peptide inhibitor, to the N-terminal amino acid of the peptide inhibitor, or to the C-terminal amino acid of the peptide inhibitor.

[00303] In additional embodiments, any of the peptide inhibitors e.g. peptides of Formulas (I)(XIV), further comprise half-life extension moiety attached to a linker moiety that is attached to an amino acid residue présent in the inhibitor, e.g., a half-life extension moiety may be bound to a linker moiety that is bound to a side chain of any amino acid of the peptide inhibitor, to the Nterminal amino acid of the peptide inhibitor, or to the C-terminal amino acid of the peptide inhibitor.

[00304] In particular embodiments, a peptide inhibitor comprises a half-life extension moiety having the structure shown below, wherein n=0 to 24 or n=I4 to 24:

128

n=0 to 24 x=ch₃, co₂h, nh₂, oh

[00305] In certain embodiments, a peptide inhibitor of the présent invention comprises a half-life extension moiety shown în Table 8.

Table 8. Illustrative Half-Life Extension Moieties

#	Half-Life Extension Moietys
Cl	0 C12 (Lauric acid)
C2	0 C14 (Mysteric acid)
C3	0 C16 (Palm or Palmitic acid)
C4	O Cl8 (Stearic acid)
C5	O C20
C6	O Ql-l C12 diacid
C7	0 H ° C14 diacid

[00306} In certain embodiments, a half-life extension moiety is bound directly to a peptide inhibitor, while in other embodiments, a half-life extension moiety is bound to the peptide inhibitor via a linker moiety, e.g., any of those depîcted în Tables l, 2 or 4,

[00307] In particular embodiments, a peptide inhibitor of the présent invention comprises any of the linker moieties shown in Tables 2 or 4 and any of the half-lîfe extension moieties shown in

Table 3, including any of the following combinations shown in Table 5.

Table 5. Illustrative Combinations of Lînkers and Half-Life Extension Moieties in Peptide

Inhibitors

Linker	Half-Life Extension Moiety		Linker	Half-Life Extension Moiety		Linker	Half-Life Extension Moiety
Ll	Cl	Ll	C2	Ll	C3
L2	Cl	L2	C2	L2	C3
L3	Cl	L3	C2	L3	C3
L4	Cl	L4	C2	L4	C3
L5	Cl	L5	C2	L5	C3
L6	Cl	L6	C2	L6	C3
L7	Cl	L7	C2	L7	C3
L8	Cl	L8	C2	L8	C3
L9	Cl	L9	C2	L9	C3
LIO	Cl	LIO	C2	LIO	C3
LH	Cl	LH	C2	LH	C3
Ll2	Cl	Ll2	C2	Ll2	C3
Ll3	Cl	Ll3	C2	Ll3	C3
Ll4	Cl	Ll4	C2	Ll4	C3
Ll5	Cl	LI5	C2	Ll5	C3

Linker	Half-Life Extension Moiety		Linker	Half-Life Extension Moiety		Linker	Half-Life Extension Moiety
Ll	C4	Ll	C5	Ll	C6
L2	C4	L2	C5	L2	C6
L3	C4	L3	C5	L3	C6
L4	C4	L4	C5	L4	C6
L5	C4	L5	C5	L5	C6
L6	C4	L6	C5	L6	C6

133

L7	C4		L7	C5		L7	C6
L8	C4	L8	C5	L8	C6
L9	C4	L9	C5	L9	C6
LIO	C4	LIO	C5	LIO	C6
LU	C4	LU	C5	LU	C6
L12	C4	Ll2	C5	Ll2	C6
L13	C4	LI3	C5	Ll3	C6
Ll4	C4	LI4	C5	L14	C6
LI5	C4	Ll5	C5	Ll5	C6

Linker	Half-Life Extension Moiety
Ll	C7
L2	C7
L3	C7
L4	C7
L5	C7
L6	C7
L7	C7
18	C7
L9	C7
LIO	C7
LH	C7
Ll2	C7
LI3	C7
Ll4	C7
Ll5	C7

Linker	Half-Life Extension Moiety
LI	C8
L2	C8
L3	C8
L4	C8
L5	C8
L6	C8
L7	C8
L8	C8
L9	C8
LIO	C8
LH	C8
Ll2	C8
Ll3	C8
Ll4	C8
LI5	C8

Linker	Half-Life Extension Moiety
Ll	C9
L2	C9
L3	C9
L4	C9
L5	C9
L6	C9
L7	C9
L8	C9
L9	C9
LIO	C9
LH	C9
Ll2	C9
Ll3	C9
Ll4	C9
Ll5	C9

Linker

Half-Life Extension Moiety

Linker

Half-Life Extension Moiety

Linker

Half-Life Extension Moiety

134

Ll	CIO		L6	CIO		LU	CIO
L2	CIO	L7	CIO	L12	CIO
L3	CIO	L8	CIO	L13	CIO
L4	CIO	L9	CIO	L14	CIO
L5	CIO	L10	CIO	L15	CIO

[00308] in some embodiments there may be multiple linkers présent between the peptide the conjugated moiety, e.g., half-life extension moiety, e.g., as depicted in Table 6.

Table 6. Illustrative Combinations of Linkers and Haif-Life Extension Moieties in Peptide

Inhibitors

Linker	Half-Life Extension Moiety
L1-L2	CIO
L2-L5-L3	CIO
L3-L8	CIO
L1-L2-L3	CIO
L5-L3-L3-L3	CIO

Linker	Half-Life Extension Moiety
L1-L2	C8
L2-L5-L3	C8
L3-L8	C8
L1-L2-L3	C8
L5-L3-L3-L3	C8

[00309] In certain embodiments, the half-life of a peptide inhibitor of the invention that includes a conjugated Chemical substituent, Le., a half-life extension moiety, is at least 100%, at least 120%, at least 150%, at least 200%, at least 250%, at least 300%, at least 400%, or at least 500% of the 10 half-life of the same peptide inhibitor but without the conjugated Chemical substituent. In certain embodiments, the lipophilie substituents and/or polypermic moieties enhance the permeability of the peptide inhibitor through the epithelium and/or its rétention in the lamina propria. In certain embodiments, the permeability through the epithelium and/or the rétention in the lamina propria of a peptide inhibitor of the invention that includes a conjugated Chemical substituent is at 100%, 15 at least 120%, at least 150%, at least 200%, at least 250%, at least 300%, at least 400%, or at least

500% of the half-life of the same peptide inhibitor but without the conjugated Chemical substituent. [00310] In certain embodiments, a side chain of one or more amino acid residues (e.g., Lys residues) in a peptide inhibitor of the invention is conjugated (e.g., covalently attached) to a lipophilie substituent. The lipophilie substituent may be covalently bonded to an atom in the amino aeid side 20 chain, or alternatively may be conjugated to the amino acid side chain via one or more spacers.

135

The spacer, when présent, may provide spacing between the peptide analogue and the lipophilie substituent. In particular embodiments, the peptide inhibitor comprises any of the conjugated moieties shown in peptides disclosed in Tables 2-6.

[00311] In certain embodiments, the lipophilie substituent may comprise a hydrocarbon chain having from 4 to 30 C atoms, for example at least 8 or 12 C atoms, and preferably 24 C atoms or fewer, or 20 C atoms or fewer. The hydrocarbon chain may be linear or branched and may be saturated or unsaturated. In certain embodiments, the hydrocarbon chain is substituted with a moiety which forms part of the attachment to the amino acid side chain or the spacer, for example an acyl group, a sulfonyl group, an N atom, an O atom or an S atom. In some embodiments, the hydrocarbon chain is substituted with an acyl group, and accordingly the hydrocarbon chain may form part of an alkanoyl group, for example palmitoyl, caproyl, lauroyl, myristoyl or stearoyl.

[00312]A lipophilie substituent may be conjugated to any amino acîd side chain in a peptide inhibitor of the invention. In certain embodiments, the amîno acid side chain includes a carboxy, hydroxyl, thiol, amide or amine group, for forming an ester, a sulphonyl ester, a thioester, an amide or a sulphonamide with the spacer or lipophilie substituent. For example, the lipophilie substituent may be conjugated to Asn, Asp, Glu, Gin, His, Lys, Arg, Ser, Thr, Tyr, Trp, Cys or Dbu, Dpr or Om. In certain embodiments, the lipophilie substituent is conjugated to Lys. An amino acid shown as Lys in any of the Formula provided herein may be replaced by, e.g., Dbu, Dpr or Om where a lipophilie substituent is added.

[00313] In certain embodiments, the peptide inhibitors of the présent invention may be modified, e.g., to enhance stability, increase permeability, or enhance drug like characteristics, through conjugation of a Chemical moiety to one or more amino acid side chain within the peptide. For example, the N(epsilon) of lysine N(epsilon), the β-carboxyl of aspartic, or the γ-carboxyl of glutamîc acid may be appropriately functionalized. Thus, to produce the modified peptide, an amino acid within the peptide may be appropriately modified. Further, in some instances, the side chain is acylated with an acylating organic compound selected from the group consisting of: Tri fluoro pentyl, Acetyl, Octonyl, Butyl, Pentyl, Hexyl, Palmityl, Trifluoromethyl butyric, cyclopentane carboxylic, cyclopropylacetic, 4-fluorobenzoic, 4-fiuorophenyl acetic, 3Phenylpropionic, tetrahedro-2H-pyran-4carboxylic, succinic acid glutaric acid or bile acids. One having skill is the art will appreciate that a sériés of conjugates can be linked, e.g., for example PEG4, isoglu and combinations thereof. One having skill is the art will appreciate that an amino acid with the peptide can be isosterically replaced, for example, Lys may be replaced for Dap, Dab, α-MeLys orOrn. Examples of modified residues within a peptide are shown in Table Ί.

136

Table 7. Examples of modified Lysine, Asp and Asn within the peptide

N^e-Lys(Ac)

O

O

N^e-Lys(Paim)

N^a-Lys-isoGîu-Palm

O

N^e-Lys(PEG)_g-Palm

N^e-Lys(succinic acid)

O

N^e-Lys(Pyroglutaric acid)

137

O	0 1
H2NY°H	h2n^°h
O	O
N®-Lys(Benzoic acid)	Ne-Lys(iVA)
O	/\^nh2 HhT
	r^o
H2N^OH	h2nVH O
U IMe-Lys(octanoic acid)	Asp(1,4 diaminobutane)
	O
HN^	J h*L/
O Asn(isobutyi)	-x / t- H J ΗΝ\Α i oh ° H2N V O N®-Lys(Biotin)

[00314] In further embodiments of the présent invention, altematively or additionally, a side-chain of one or more amino acid residues in a peptide inhibitor of the invention is conjugated to a polymeric moiety, for example, in order to increase solubility and/or half-life in vivo (e.g, in 5 plasma) and/or bioavailability. Such modifications are also known to reduce clearance (e.g. rénal clearance) of therapeutic proteins and peptides.

[00315] As used herein, “Polyethylene glycol” or “PEG” is a polyether compound of general Formula H-(O-CH2-CH2)n-OH. PEGs are also known as polyethylene oxides (PEOs) or polyoxyethylenes (POEs), depending on their molecular weight PEO, PEE, or POG, as used 10 herein, refers to an oligomer or polymer of ethylene oxide. The three names are chemically synonymous, but PEG has tended to refer to oligomers and polymers with a molecular mass below 20,000 Da, PEO to polymers with a molecular mass above 20,000 Da, and POE to a polymer of any molecular mass. PEG and PEO are liquids or low-melting solids, depending on their molecular weights. Throughout this disclosure, the 3 names are used indistinguishably. PEGs are prepared

138 by polymenzation of ethylene oxide and are commercially available over a wide range of molecular weights from 300 Da to 10,000,000 Da. While PEG and ΡΕΟ with different molecular weights find use in different applications, and hâve different physîcal properties (e.g. viscosity) due to chain length effects, their Chemical properties are nearly identical. The polymerîc moiety is preferably water-solubie (amphiphilic or hydrophilic), non-toxic, and pharmaceutically inert. Suitable polymerîc moieties include polyethylene glycols (PEG), homo- or co-polymers of PEG, a monomethyl-substituted polymer of PEG (mPEG), or polyoxyethylene glycerol (POG). See, for example, Int. J. Hematology 68:1 (1998); Bîoconjugate Chem. 6:150 (1995); and Crit. Rev. Therap. Drug Carrier Sys. 9:249 (1992). Also encompassed are PEGs that are prepared for purpose of half life extension, for example, mono-activated, alkoxy-terniinated polyaikylene oxides (POA’s) such as mono-methoxy-terminated polyethyelene glycols (mPEG’s); bis activated polyethylene oxides (glycols) or other PEG dérivatives are also contemplated. Suitable polymers will vary substantially by weights ranging from about 200 Da to about 40,000 Da or from about 200 Da to about 60,000 Da are usually selected for the purposes ofthe present invention. In certain embodiments, PEGs having molecular weights from 200 to 2,000 or from 200 to 500 are used. Different forms of PEG may also be used, depending on the initiator used for the polymerization process - a common common initiator is a monofunctîonal methyl ether PEG, or methoxypoly(ethylene glycol), abbreviated mPEG.

[00316] Lower-molecular-weight PEGs are also available as pure oligomers, referred to as monodisperse, unîform, or discrète. These are used in certain embodiments of the present invention.

[00317] PEGs are also available with different géométries: branched PEGs hâve three to ten PEG chains emanating from a central core group; star PEGs hâve 10 to 100 PEG chains emanating from a central core group; and comb PEGs hâve multiple PEG chains normally grafted onto a polymer backbone. PEGs can also be linear. The numbers that are often included in the names of PEGs indicate their average molecular weights (e.g. a PEG with n = 9) would hâve an average molecular weight of approximately 400 daltons, and would be labeled PEG 400.

[00318]As used herein, “PEGylation” is the act of covalently coupling a PEG structure to the peptide inhibitor of the invention, which is then referred to as a “PEGylated peptide inhibitor”. In certain embodiments, the PEG of the PEGylated side chain is a PEG with a molecular weight from about 200 to about 40,000. In some embodiments, a spacer of a peptide of Formula I, Formula F, or Formula I” is PEGylated. In certain embodiments, the PEG of a PEGylated spacer is PEG3, ) 139

PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG 10, or PEGl l. In certain embodiments, the PEG of a PEGylated spacer is PEG3 or PEG8.

[00319] Other suitable polymeric moieties include poly-amino acids such as poly-lysine, polyaspartic acid and poly-glutamic acid (see for example Gombotz, et al. (1995), Bioconjugate Chem., 5 vol. 6: 332-351; Hudecz, et al. (1992), Bioconjugate Chem., vol. 3, 49-57 and Tsukada, et al.

(1984), J. Natl. Cancer Inst., vol. 73, : 721-729. The polymeric moiety may be straight-chain or branched. In some embodiments, it has a molecular weight of 500-40,000 Da, for example 50010,000 Da, 1000-5000 Da, 10,000-20,000 Da, or 20,000-40,000 Da.

100320] In some embodiments, a peptide inhibitor of the invention may comprise two or more such 10 polymeric moieties, in which case the total molecular weight of ail such moieties will generally fall within the ranges provided above,

[00321] In some embodiments, the polymeric moiety is coupled (by covalent linkage) to an amino, carboxyl or thiol group of an amino acid sîde chain. Certain examples are the thiol group of Cys residues and the epsilon amino group of Lys residues, and the carboxyl groups of Asp and Glu 15 residues may also be invoived.

[00322] The ski lied worker will be well aware of suitable techniques which can be used to perform the coupling reaction. For example, a PEG moiety bearing a methoxy group can be coupled to a Cys thiol group by a maleimido linkage using reagents commercially available from Nektar Therapeutics AL. See also WO 2008/101017, and the references cited above, for details of suitable 20 chemistry. A maleimide-functionalised PEG may also be conjugated to the side-chain sulfhydryl group of a Cys residue.

[00323] As used herein, disulfide bond oxidation can occur within a single step or is a two step proeess. As used herein, for a single oxidation step, the trityl protecting group is often employed during assembly, allowing deprotection during cleavage, followed by solution oxidation. When a 25 second disulfide bond is required, one has the option of native or sélective oxidation. For sélective oxidation requiring orthogonal protecting groups, Acm and Trityl is used as the protecting groups for cysteine. Cleavage results in the removai of one protecting pair of cysteine allowing oxidation of this pair, The second oxîdative deprotection step of the cysteine protected Acm group is then performed. For native oxidation, the trityl protecting group is used for ail cysteines, allowing for 30 natural folding of the peptide. A ski lied worker will be well aware of suitable techniques which can be used to perform the oxidation step.

[00324] Several Chemical moieties, including poly(ethylene)glycol, react with functional groups présent in the twenty naturally occurrîng amino acids, such as, for example, the epsilon amino

140 group in lysine amino acid residues, the thiol présent m cysteine amino acid residues, or other nucleophilic amino acid side chains. When multiple naturally occurring amino acids react in a peptide inhibitor, these non-specific Chemical reactions resuit in a final peptide inhibitor that contains many isomers of peptides conjugated to one or more poly(ethylene)glycol strands at different locations within the peptide inhibitor.

[00325] One advantage of certain embodiments of the présent invention includes the ability to add one or more Chemical moiety (such as PEG) by incorporating one or more non-natural amino acid(s) that possess unique functîonal groups that react with an activated PEG by way of chemistry that is unreactive with the naturally occurring amino acids présent in the peptide inhibitor. For example, azide and alkyne groups are unreactive with ail naturally occurring functîonal groups in a protein. Thus, a non-natural amino acid may be incorporated in one or more spécifie sites in a peptide inhibitor where PEG or another modification is desired without the undesirable nonspecific reactions. In certain embodiments, the particular chemistry involved in the reaction results in a stable, covalent link between the PEG strand and the peptide inhibitor. In addition, such reactions may be performed in mild aqueous conditions that are not damaging to most peptides. In certain embodiments, the non-natural amino acid residue is AHA.

[00326] Chemical moieties attached to natural amino acids are limited in number and scope. By contrast, Chemical moieties attached to non-natural amino acids can utilize a significantly greater spectrum of useful chemistries by which to attach the Chemical moiety to the target molécule. Essentially any target molécule, including any protein (or portion thereof) that includes a nonnatural amino acid, e.g., a non-natural amino acid containing a reactive site or side chain where a Chemical moiety may attach, such as an aldéhyde- or keto-derivatized amino acid, can serve as a substrate for attaching a Chemical moiety.

[00327]Numerous chemical moieties may be joined or linked to a particular molécule through various known methods in the art. A variety of such methods are described in U.S. Patent No. 8,568,706. As an illustrative example, azide moieties may be useful in conjugating chemical moieties such as PEG or others described herein. The azide moiety serves as a reactive functîonal group, and is absent in most naturally occurring compounds (thus it is unreactive with the native amino acids of naturally occurring compounds). Azides also undergo a sélective ligation with a lîmited number of reaction partners, and azides are small and can be introduced to biological samples without altering the molecular size of significantly. One reaction that allows incorporation or introduction of azides to molécules is the copper-mediated Huisgen [3+2] cycloaddition of an azide. This reaction can be used for the sélective PEGylation of peptide inhîbîtors. (Tomoe et al.,

141

J. Org. Chem. 67: 3057, 2002; Rostovtsev et al., Angew. Chem., Int. Ed. 41: 596, 2002; and Wang et al., J. Am. Chem. Soc. 125: 3192, 2003, Speers et al., J. Am. Chem. Soc., 2003, 125, 4686). Synthesis of Peptide Inhibitors

[00328]The peptide inhibitors of the présent invention may be synthesized by many techniques that are known to those ski lied in the art. In certain embodiments, monomer subunits are synthesized, purified, and dimerized using the techniques described in the accompanying Examples. In certain embodiments, the present invention provides a method of producing a peptide inhibitor (or monomer subunit thereof) of the present invention, comprising chemically synthesizing a peptide comprising, consisting of, or consisting essentîally of a peptide having an amino acid sequence described herein, including but not limited to any of the amino acid sequences set forth in any of Formulas I, II or tables herein. In other embodiments, the peptide is recombinantly synthesized, instead of being chemically synthesized. In certain embodiments, the peptide inhibitor is a dimer, and the method comprises synthezing both monomer subunits of the peptide dimer inhibitor and then dimerizing the two monomer subunits to produce the peptide dimer inhibitor. In varions embodiments, dîmerization is accomplished via any of the varions methods described herein. In particular embodiments, methods of producing a peptide inhibitor (or monomer subunit thereof) further comprise cyclizing the peptide inhibitor (or monomer subunit thereof) after its synthesis. In particular embodiments, cyclization is accomplished via any of the varions methods described herein. In certain embodiments, the present invention provides a method of producing a peptide inhibitor (or monomer subunit thereof) of the present invention, comprising introducing an întramolecular bond, e.g., a disulfide, an amide, or a thioether bond between two amino acids residues within a peptide comprising, consisting of, or consisting essentîally of a peptide having an amino acid sequence described herein, including but not limited to any of the amino acid sequences set forth in any of Formulas (I) - (IX), the accompanying Examples or Tables.

[00329] In related embodiments, the present invention includes polynucleotides that encode a polypeptide having a sequence set forth in any one of Formulas (I)-(IX), or the accompanying Examples or Table.

[00330] In addition, the present invention includes vectors, e.g., expression vectors, comprising a polynucleotide of the present invention.

METHODS OF TREATMENT

[00331] In certain embodiments, the present invention includes methods of inhibiting IL-23 bînding to an IL-23R on a cell, comprising contacting the IL-23 with a peptide inhibitor of the present

142 invention. In certain embodiments, the cell is a mammahan cell. In particular embodiments, the method is performed in vitro or in vivo. Inhibition of binding may be determined by a variety of routine experimental methods and assays known in the art.

[00332] In certain embodiments, the present invention includes methods of inhibiting IL-23 signaling by a cell, comprising contacting the IL-23 wîth a peptide inhibitor of the present invention. In certain embodiments, the cell is a mammalian cell. In particular embodiments, the method is performed in vitro or in vivo. In particular embodiments, the inhibition of IL-23 signalling may be determined by measuring changes in phospho-STAT3 levels in the cell.

|00333[In some embodiments, the present invention provides methods for treating a subject afflicted with a condition or indication associated with IL-2] or 1L-23R (e.g., activation of the IL23/IL-23 R signaling pathway), wherein the method comprises administering to the subject a peptide inhibitor of the present invention. In certain embodiments, a method is provided for treating a subject afflicted with a condition or indication characterized by inappropriate, deregulated, or increased IL-23 or IL-23R activity or signaling, comprising administering to the individual a peptide inhibitor of the present invention in an amount sufficient to inhibit (partially or fully) binding of IL-23 to IL-23R in the subject. In particular embodiments, the inhibition of IL-23 binding to IL-23R occurs in particular organs or tissues of the subject, e.g., the stomach, small intestine, large întestîne/colon, intestinal mucosa, lamina propria, Peyer’s Patches, mesenteric lymph nodes, or lymphatic ducts.

[0033411η some embodiments, methods of the present invention comprise providing a peptide inhibitor of the present invention to a subject in need thereof. In particular embodiments, the subject in need thereof has been diagnosed with or has been determined to be at risk of developing a disease or disorder associated with IL-23/IL-23R. In particular embodiments, the subject is a mammal.

[00335] In certain embodiments, the disease or disorder is autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, inflammation of the gut, inflammatory bowel diseases (IBDs), juvénile 1BD, adolescent IBD, Crohn’s disease, ulcerative colitis, sarcoidosis, Systemic Lupus Erythematosus, ankylosing spondylitis (axial spondyloarthritis), psoriatic arthritis, or psoriasis. In particular embodiments, the disease or disorder îs psoriasis (e.g., plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, Palmo-Plantar Pustulosis, psoriasis vulgaris, or érythrodermie psoriasis), atopie dermatitis, acné ectopica, ulcerative colitis, Crohn’s disease, Celiac disease (nontropical Sprue), enteropathy associated with séronégative arthropathies, microscopie colitis, collagenous colitis, éosinophilie

143 gastroenteritis/esophagitîs, colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency-1, chronic granulomatous disease, glycogen storage disease type lb, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wîskott-Aldrîch Syndrome, pouchitis, pouchîtis resulting after proctocolectomy and 5 ileoanal anastomosîs, gastrointestinal cancer, pancreatîtis, insulin-dependent diabètes mellitus, mastitis, cholecystitis, cholangitis, primary biliary cirrhosis, viral-associated enteropathy, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, uveitis, or graft versus host disease. [00336] In certain embodiments, the présent invention provides methods for treating an inflammatory bowel disease (IBD) in a subject in need thereof, comprisîng administering to the 10 subject a peptide inhibitor of the présent invention,wherein the peptide inhibitor comprises or consists of an amino acid sequence of Formula (I). In certain embodiments, the IBD is ulcerative colitis. In certain embodiments, the IBD is Crohn’s disease. In certain embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of Formula (Z) or (Z’). In certain embodiments, the IBD is ulcerative colitis. In certain embodiments, the IBD is Crohn’s disease.

[00337] In certain related embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of Formula (la), (ïb), (le), or (Id). In certain embodiments, the IBD îs ulcerative colitis. In certain embodiments, the IBD is Crohn’s disease.

[00338] In other related embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of Formula (lia), (Ilb), or (11c). In certain embodiments, the IBD is ulcerative colitis. In 20 certain embodiments, the IBD is Crohn’s disease.

[00339] In other related embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of Formula (Ilia), (Hlb), (Ilk), or (Illd). In certain embodiments, the IBD is ulcerative colitis. In certain embodiments, the IBD is Crohn’s disease.

[00340] In other related embodiments, the peptide inhibitor comprises or consists of an amino acid 25 sequence of Formula (IVa), (IVb), (IVc), (IVd), (IVe), (ÎVQ_t (IVg), or (IVh). In certain embodiments, the IBD is ulcerative colitis. In certain embodiments, the IBD is Crohn’s disease.

[00341] In other related embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of Formula (Va), (Vb), (Ve), or (Vd). In certain embodiments, the IBD is ulcerative colitis. In certain embodiments, the IBD is Crohn’s disease.In other related embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of Formula (Via), (VIb), (VIc), (VId), (Vie), (Vif), (VIg), or (Vlh). In certain embodiments, the IBD is ulcerative colitis. In certain embodiments, the IBD is Crohn’s disease.

144

[00342) In other related embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of Formula (Vlla), (VIIb), (Vile), or (Vlld). In certain embodiments, the IBD is ulcerative colitis. In certain embodiments, the IBD is Crohn’s disease.

[00343] In other related embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of Formula (Villa), (Vlllb), (Ville), (Vllld), (Ville), (VUIf), (VlIIg), or (VUIh). In certain embodiments, the IBD is ulcerative colitis. In certain embodiments, the IBD is Crohn’s disease.

[00344] In other related embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of Formula (IXa), (IXb), (IXe), or (IXd). In certain embodiments, the IBD îs ulcerative colitis. In certain embodiments, the IBD is Crohn’s disease.

[00345] In other related embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of Formula (Xa), (Xb), (Xc), (Xd), (Xe), (Xf), (Xg), or (Xh). In certain embodiments, the IBD is ulcerative colitis. In certain embodiments, the IBD is Crohn’s disease.

|00346) In other related embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of Formula (Xla), (Xlb), (XIc), or (Xld). In certain embodiments, the IBD is ulcerative colitis. In certain embodiments, the IBD îs Crohn’s disease.

[00347] In other related embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of Formula (Xlla), (XHb), (XIIc), (Xlld), (Xlle), (Xllf), (Xllg), or (Xllh). In certain embodiments, the IBD is ulcerative colitis. In certain embodiments, the IBD is Crohn’s disease.

[00348] In other related embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of Formula (XlIIa), (XlIIb), (XIIIc), or (XlIId). In certain embodiments, the IBD is ulcerative colitis. In certain embodiments, the IBD is Crohn’s disease.

[00349] In other related embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of Formula (XlVa), (XlVb), (XIVc), (XlVd), (XlVe), (XlVf), (XlVg), or (XlVh). In certain embodiments, the IBD is ulcerative colitis. In certain embodiments, the IBD îs Crohn’s disease.

[00350] In other related embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of Formula (XVa), (XVb), (XVc), or (XVd). In certain embodiments, the IBD is ulcerative colitis. In certain embodiments, the IBD is Crohn’s disease.

[00351] In other related embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of Formula (XVIa), (XVIb), (XVIc), (XVId), (XVle), (XVIf), (XVIg), or (XVIh). In certain embodiments, the IBD is ulcerative colitis. In certain embodiments, the IBD is Crohn’s disease.

145

[00352] In other related embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of Formula (XVIIa), (XVllb), (XVIIc), or (XVIId). In certain embodiments, the IBD is ulcerative colitis. In certain embodiments, the IBD is Crohn’s disease.

[00353] In other related embodiments, the peptide inhibitor comprises or consists of an amino acid sequence of Formula (Z’), (Z’-A), (Z’-B), (Z’-C), (Z’-D), (Z’-E), (Z’-F), (Z’-G), (Z’-H), (Z’-I), (Z’-J), (Z’-K), (Z’-L), or (Z’-M). In certain embodiments, the IBD is ulcerative colitis. In certain embodiments, the IBD is Crohn’s disease.

[00354] In certain related embodiments of methods of treating an IBD, e.g., ulcerative colitis or Crohn’s disease, the peptide inhibitor comprises or is any one of the amino acid sequence listed below; or a pharmaceutically acceptable sait thereof

Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Ph)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-dK-[Sarc]-NH₂ (SEQ ID NO:1);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-amînoethoxy)]-[3-Quin]-[a-MeLys][Lys(Ac)]-N-[(D)Leu)]-[Sarc]-NH₂ (SEQ ID NO:2);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[THP]-E-N[(D)Lys]-[Sarc]-NH₂ (SEQ ID NO:3);

Ac-[Pen]-N-T-[W(7-Me)}-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[a-MeLys][Lys(Ac)]-N-[(D)His]-[Sarc]-NH₂ (SEQ ID NO:4);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-E3-Quin]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:5);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[THP]-E-N[(D)Leu)]-[Sarc]-NH₂ (SEQ IDN0:6);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[a-MeLys][Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂ (SEQ ID NO:7);

Ac-[(D)Arg]-[Abu]-Q-T-W-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-N[(D)NMeTyr]-NH₂ (SEQ ID NO:8);

Ac-[(D)Arg]-[Pen]-Q-T-W-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-N[(D)NMeTyr]-NH₂ (SEQ IDNO:9);

Ac-[(D)Arg]-[Pen]-Q-T-W-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[aMeGlu]-N-F[(D)NMeTyr]-NH₂ (SEQ ID NO:I0);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)HPen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-E-N[(D)Lys]-[Sarc]-NH₂ (SEQ ID NO:11);

146

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[a-MeLys][Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂ (SEQ ID NO: 12);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-E-N[(D)Leu]-[Sarc]-NH₂ (SEQ ID NO:13);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[a-MeLys]“ [Lys(Ac)]-N-[(D)Leu]-[Sarc]-NH₂ (SEQ ID NO:14);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-E-N-H[Sarc]-NH₂ (SEQ IDNO:15);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID N0:16);

Ac-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂ (SEQ IDN0:17);

Ac-[Abu]-Q-T-[W(7-Ph)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2 (SEQ ID NO: 18);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-ammoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Leu]-[Sarc]-NH₂ (SEQ ID NOs:20, 25);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂ (SEQ ID NO:21);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂ (SEQ IDNO:22);

Ac-[Pen]-N-T-[W(7-Me)}-[Lys(Ac)]-[Pen]-Phe[4-(2-aminOethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:23);

Ac-[Pen]-N-T-[W(7-Me)HLys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[(D)Leu]-[Sarc]-NH₂ (SEQ IDNO:24);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Leu]-[Sarc]-NH₂ (SEQ ID NO:25);

Ac’[Pen]-N-T-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂ (SEQ ID NO:26);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:27);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Gly)l-[Pen]-Phe[4-(2-aminoethoxy)J-[2-Nal]-[THP]-E-N[(D)Leu]-[Sarc]-NH₂ (SEQ ID NO:28);

147

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-amÎnoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Leu]-[Sarc]-NH₂ (SEQ ID NO:29);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(bAla)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂ (SEQ ID NO:30);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(bAla)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:31 );

Ac-[Pen]-N-T-[W(7-Et)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂ (SEQ 1DNO:32);

Ac-[Pen]-N-T-[W(7-Et)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:33);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-Et)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:34);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2~aminoethoxy)]-[W(4-Me)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:35);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(6-Me)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:36);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(4'OMe)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:37);

Ac-[Pen]-N-T-[W(7-Me)HLys(Ac)HPen]-Phe[4-(2-aminoethoxy)]-[W(7-i-Pr)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:38);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-nPr)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:39);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-OMe)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:40);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(6-CI)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO;41);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(5-OMe)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:42);

Ac-[Pen]-N-T-[W(7-Me)HLys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(3-MePh)Ha-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:43);

Ac-[Pen]-N-T-[W(7-Me)HLys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(6-Ph)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:44);

B MS

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(6-Et)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:45);

Ac-[Pen]-N-T-[W(7-(2-FPh)]- [Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-(2-Nal]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:46);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Leu]-[(D)NMeTyr]-NH₂ (SEQ ID NO:47);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Lys]-[(D)NMeTyr]-NH₂ (SEQ ID NO:48);

Ac-[Pen]-N-T-[W(7-(2-OMePh)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]I0 [Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:49);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-Ph)]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:50);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID N0:51);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂ (SEQ ID NO:52);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)HPen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-E-N-H[Sarc]-NH₂ (SEQ ID NO:53);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-S-H20 [Sarc]-NH₂ (SEQ ID NO:54);

Ac-[Pen]-S-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂ (SEQ ID NO:55);

Ac-[Pen]-S-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-S-H[Sarc]-NH₂ (SEQ ID NO:56);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[(D)NMeTyr]-NH₂ (SEQ ID NO:57);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-F-[(D)NMeTyr]-NH₂ (SEQ ID NO:58);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-S-H30 [Sarc]-NH₂ (SEQ ID NO;59);

Ac-[Pen]-S-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂ (SEQ ID NO:60);

Φ ¹⁴⁹

Ac-[Pen]-S-T-[W(7-Ph)]-[Lys(Ac)]-(Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-S-H[Sarc]-NH₂ (SEQ ID NO:61 );

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[(D)NMeTyr]-NH₂(SEQ IDNO:62);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-[(D)Asn]H-[Sarc]-NH₂ (SEQ ID NO:63);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-G-H[Sarc]-NH₂ (SEQ ID NO:64);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-[h(Ser)]10 H-[Sarc]-NH₂ (SEQ ID NO:65);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H-PNH₂ (SEQ ID NO:66);

Ac-[Pen]-N-T-[W(7-(2-Nal))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂ (SEQ ID NO:67);

Ac-[Pen]-N-T-[W(7-3BiPh)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂ (SEQ ID NO:68);

Ac-[Pen]-N'T-[W(7-(Phenanthren-5-yl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-H-[Sarc]-NH₂ (SEQ ID NO:69);

Ac-[Pen]-N-T-[W(7-(4-Anthracen-5-yl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]20 [THP]-E-N-H-[Sarc]-NH₂ (SEQ ID NO:70);

Ac-[Pen]-N-T-[W(7-(l-Nal))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂ (SEQ IDNO:71);

Ac-[Pen]-N-T-[W(7-(4BiPh))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH2 (SEQ ID NO:72);

Ac-[Pen]-N-T-[W(7<3,5-t-Bu-Ph))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-H-[Sarc]-NH₂ (SEQ IDNO:73);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[THP]-E-N-H-[Sarc]-NH₂ (SEQ ID NO:74);

Ac-[Pen]-N-T-[W(7-Me)HLys(Ac)]-[Pen]-[Phe(4-OMe)]-[2-Nal]-[THP]-E-N-H-[Sarc]-NH2 (SEQ IDNO:75);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)M3Quin]-[a-MeLys][Lys(Ac)]-N-[2Pal]-NH₂ (SEQ ID NO:78);

150

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[2Pal]-NH₂ (SEQ ID NO:79);

Ac-|Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-NH₂ (SEQ ID NO:80);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]N-H-[Sarc]-NH₂ (SEQ ID NO:81);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-[(D)NMeTyr]-NH₂ (SEQ ID NO:82);

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Eys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-E-N-H-[(D)NMeTyr]-NH₂ (SEQ ID NO:83);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-Phe[4-aminomethyl]-[(D)NMeTyr]-NH2 (SEQ IDNO:84);

Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-'Nal]-[aMeLeu]-[Lys(Ac)]-N[(D)His]-NH₂ (SEQ ID NO:85);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)His]-NH2 (SEQ ID NO:86);

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-ammoethoxy)]-[2-NalHTHP]-EN-[(D)Hîs]-[(D)NMeTyr]-NH₂ (SEQ ID NO;87);

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-N-[(D)NMeTyr]-NH₂ (SEQ ID NO:88);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-N-[(D)NMeTyr]-NH₂ (SEQ ID NO:89);

Ac~[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Val]-[(D)NMeTyr]-NH₂ (SEQ ID NQ:90);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy )]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Thr]-[(D)NMeTyr]-NH₂ (SEQ ID NO:91);

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)HPen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(D)His]-NH₂ (SEQ ID NO:92);

Ac-[Abu]-N-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[3Quiri]-[THP]-E-N-H-[Sarc]-NH₂ (SEQ IDNO:93);

Ac-[Abιl]-N-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-E-N-H-[Sarc]-Nl·I₂ (SEQ ID NO:94);

151

Ac-[Abu]-N-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-la-MeLys]-[Lys(Ac)]-N-H[Sarc]-NH₂ (SEQ ID NO:95);

Ac-[Abu]-N-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nai]-[THP]-E-N-H-[Sarc]-NH₂ (SEQ ID NO:96);

Ac-[Abu]-N-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH₂ (SEQ ID NO:97);

Ac-[Abu]-N-T-[W(7-Ph))-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂; (SEQ ÎD NO:98)

Ac-[Abu]-N-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)[-[2-NalHTHP]-E-N-H[Sarc]-NH₂ (SEQ ID NO:99);

Ac-[(D)Arg]-[Abu]-S-T-[W(7-Me)]-Q-[Cys]-Phe(4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂(SEQ ID NO: 100);

Ac-[(D)Arg]-[Abu]-N-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)H2-NaIHTHP]-E-N[(D)Leu]-[Sarc]-NH₂(SEQ ID NO: 101);

Ac-[(D)Arg]-[Abu]-N-T-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH₂(SEQ ID NO: 102);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-[Sarc]-NH₂(SEQ IDNO:103);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂(SEQ ID NO:104);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe|4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-[Sarc]-NH₂(SEQ ID NO: 105);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂(SEQ ID NO:106);

Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Na[]-[THP]-E-N-[3Pal][Sarc]-NH₂(SEQ IDNO:i07);

Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[TIIP]-E-N-[3Pal]-[Sarc]NH₂(SEQ ID NO: 108);

Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)H2-Nal]-[THP]-E-N-[3Palj-[Sarc]NH₂(SEQ IDNO:109);

Ac-[Abu]-Q-T-[W(7-Me)}-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-NalHa-MeLys]-[Lys(Ac)]-N[3Pa!]-[Sarc]-NH₂ (SEQ ID NO: 1 10);

B 152

Ac-[Abu]-Q-T-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3PalJ[Sarc]-NH₂ (SEQ ID NO: I H );

Ac-[Abu]-Q-T-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:112);

Ac-fAbu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[bA]NH₂ (SEQ ID N0:ll3);

Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-S-[3Pal]-[bA]NH₂ (SEQ ID NO: H 4);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[4Pal]10 [Sarc]-NH₂ (SEQ IDNO:ll5);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][bA]-NH₂ (SEQ ID NO: 116);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂ (SEQ IDNO:l 17);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Quin]-[Sarc]-NH₂ (SEQ ID NO: 118);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[TIIP]-E-N-[ 7Aza-tryptophan]-[Sarc]-NH₂ (SEQ ID NO: 119);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-amÎnoethoxy)]-[2-Nal]-[a-MeLys]20 [Lys(Ac)]-N-[3Pal]-[(D)aMeTyr]-NH₂ (SEQ ID NO: 120);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-(Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][(D)aMeTyr]-NH₂ (SEQ ID NO:l21);

Ac-[Pen]-N-T-(W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-[(D)aMeTyr]-NH₂ (SEQ ID NO:l22);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pa[][(D)aMeTyr]-NH₂ (SEQ ID NO:l23);

Ac-[Pen]-S-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)|-[2-Nal]-[THP]-E-S-[3Pal][Sarc]-NH₂ (SEQ ID NO:l24);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-S-[3Pal]30 [Sarc]-NH₂ (SEQ IDNO:l25);

Ac-[Pen]-N-T-[W(7-Ph)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH₂ (SEQ ID NO:I26);

B 153

Ac-[Pen]-N-T-[W(7-Ph)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-NaI]-[Tl·IP]-E-N-[3Pal]-[Sarc]NH₂ (SEQ ID NO:127);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen|-Phe[4-(2-amÎnoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-[bA]-NH₂ (SEQ ID NO: 130);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]’[2-Nal]-[THP]-E-N-[3Pal][bA]-NH₂(SEQ ID NO:131);

Ac-[Pen]-S-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂(SEQ ID NO: 132);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]’[THP]-[Lys(Ac)]10 N-[3Pal]-[Sarc]-NH₂(SEQ IDNO:133);

Ac-[Abu]-Q-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)}-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH₂(SEQ ID NO: 134);

Ac-[Abu]-Q-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂(SEQ IDNO:135);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂(SEQ ID NO: 136);

Ac-[Pen]-N-T-(W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aceylaminoethoxy)]-[2-Nal]-[THP][Lys(Ac)]-N-[3Pal]-[Sarc]-NH₂(SEQ ID NO: 137);

Ac-[Pen]-E-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]20 N-[3Pal]-[Sarc]-NH₂(SEQ ID NO: 138);

Ac-[Pen]-E-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂(SEQ ID NO: 139);

Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH₂ (SEQ ID NO: 140);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO: 141);

Ac-[Pen]-N-T-[W(7-(3-carboxamidophenyl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:142);

Ac-[Pen]-N-T-[W(7-pyrimidin-5-yl)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]30 E-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO: 143);

Ac-[Pen]-N-T-[W(7-imidazopyridinyl)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aininoethoxy)]-[2-Nal][THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQ IDNO:144);

B 154

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMe(Lys)][Lys(Ac)]-N-[His_3Me]-NH₂ (SEQ ID NO:145);

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[His_3Me]-NH₂ (SEQ ID NO:146);

Ac-[Pen]-N-T-[W(7-(4Quin))]-[Lys(Ac)HPen]-Phe[4-(2-amÎnoethoxy)]-[2-NalHTHP]-E-N[3Pal]-[Sarc]-NH₂ (SEQ IDNO:147);

Ac-[Pen]-N-T-[(W(7-(3-pyrazol-l-yl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-amînoethoxy)]-[2-Nal][THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO: 148);

Ac-[Pen]-N-T-[(W(7-(5-Et-Ph))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N10 [3Pal]-[Sarc]-NH₂ (SEQ ID NO: 149);

Ac-[Pen]-N-T-[W(5-Ph)]-(Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ ID NO:150);

Ac-[Pen] -N -T- [( W (7-(3 -py razol -1 -y I ))] - [Ly s(Ac)]- [Pen] -Phe [4-(2-am i noethoxy)] - [2-Nal ] [THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO: 151 );

Ac-[Pen]-N-T-[W(7-indazol-5-yI)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH₂(SEQ ID NO: 152);

Ac-[Pen]-N-T-[W(4-F)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3PaJ][Sarc]-NH₂ (SEQ ID NO: 153);

Ac-[Pen]-N-T-[W(5-CN)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]20 [Sarc]-NH₂ (SEQ ID NO: 154);

Ac-[Pen]-N-T-[W(7-CN)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ ID NO:155);

Ac-[Pen]-N-T-[W(4-OMe)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Pal]-[Sarc]-NH₂ (SEQ IDNO:156);

Ac-[Pen]-N-T-[W(4-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ ID NO; 157);

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH₂(SEQ ID NO:158);

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-E-N-[3Pal]-[Sarc]30 NH₂ (SEQ ID NO: 159, 285);

Ac-[Pen]-N-T-[W(5-Ca)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc] -NH₂ (SEQ ID NO : 160);

B 155

Ac-[Pen]-N-T-[Trp_4Aza]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ ID NO:161);

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH₂ (SEQ ID NO: 162);

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal][Sarc]-NH₂ (SEQ ID NO: 163);

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)J-[Lys(Ac)]-IPen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(5Pyal)]-NH₂ (SEQ IDNO:164);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-Me-Lys]10 [Lys(Ac)]-N-[(5Pyal)]-NH₂ (SEQ ID NO:165);

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(l-Me)His|-NH> (SEQ ID NO: 166);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys][Lys(Ac)]-N-[(l-Me)His]-NH₂ (SEQ ID NO: 167); or

Ac-[Pen]-N -T-[W(7-Me]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-Me-Lys][Lys(Ac)]-N-[3Pal]-[(D)NMeTyr]-NH₂ (SEQ ID NO: 168);

and wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or via an Abu-C thioether bond.

[00355] In certain related embodiments of methods of treating an IBD, e.g., ulcerative colitis or 20 Crohn’s disease, the peptide inhibitor comprises or is any one of the amino acid sequence listed below; or a pharmaceutically acceptable sait thereof:

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-NH₂ (SEQ ID NO:80);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-(2-Nal]-[THP]-E-N-[3Pal]25 [Sarc]-NH₂ (SEQ ID NO: 104);

Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH₂ (SEQ ID NO: 108);

Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂ (SEQ ID NO:110);

Ac-[Abu]-Q-T-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:112);

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal ]-[THP]-E-N[3Quin]-[Sarc]-NH_;i (SEQ ID NO:118);

B 156

Ac-[Pen]-S-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-S-[3Pal][Sarc]-NH₂ (SEQ ID NO:124); or

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)H2-Nal]-[THP]-E-S-[3PaI][Sarc]-NH₂ (SEQ ID NO:125);

and wherein the peptide inhibitor is cyclized via a Pen-Pen disulfïde bond; or via an Abu-Cys thioether bond.

[00356] In certain related embodiments of methods of treating an IBD, e.g., ulcerative colitis or Crohn’s disease, the peptide inhibitor comprises or is any one of the amino acid sequence listed below; or a pharmaceutically acceptable sait thereof:

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO: 105);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ ID NO:106);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)H2-Nal]-[THP]-[Lys(Ac)]-N15 [3Pai]-[Sarc]-NH₂ (SEQ ID NO: 117);

Ac-[Pen]-N-T-[W(7-Ph)]-[Cit]-[Peii]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH₂ (SEQ ID NO: 126);

Ac-[Pen]-N-T-[W(7-Ph)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH₂ (SEQ IDNO:127);

Ac-[Abu]-Q-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH₂ (SEQ ID NO: 134);

Ac-[Abu]-Q-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂ (SEQ ID NO: 135);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)j-[2-Nal]-[THP]-[Lys(Ac)]-N25 [3Pal]-[Sarc]-NH₂ (SEQ ID NO: 136);

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aceylaminoethoxy)]-[2-Nal]-[THP][Lys(Ac)]-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO: 137); or

Ac-[Pen]-E-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂ (SEQ ID NO: 139);

and wherein the peptide inhibitor is cyclized via a Pen-Pen disulfïde bond; or via an Abu-C thioether bond.

B 157

[00357]In certain related embodiments of methods of treating an IBD, e.g., ulcéra tîve colitis or Crohn’s disease, the peptide inhibitor comprises or is any one of the amino acid sequence listed below; or a pharmaceutically acceptable sait thereof:

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal}-[a-MeLys]-[Lys(Ac)]-N5 [3Pal]-[Sarc]-NH₂ (SEQ ID NO: 139);

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH₂ (SEQ ID NOs:I58, 162, 284);

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal][Sarc]-NH₂ (SEQ ID NO: 163);

Ac-[Pen]-N-T-W-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:523);

Ac-[Pen]-N-T-W-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQ

ID NO:524);

Ac-[Abu]-Q-T-W-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2 (SEQ 1DNO:525);

Ac-[Abu]-Q-T-W-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal][Sarc]-NH₂ (SEQ ID NO;526);

Ac-[Pen]-N-T-W-[Eys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal][Sarc]-NH₂ (SEQ ID NO:163);

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aceylaminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂ (SEQ ID NO;527);; or

Ac-[Pen]-E-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal][Sarc]-NH₂ (SEQ ID NO:528);

and wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or via an Abu-C thioether bond.

[00358] In certain related embodiments of methods of treating an IBD, ulcerative colitis or Crohn’s disease, the peptide inhibitor comprises or is any one of the amino acid sequence listed below; or a pharmaceutically acceptable sait thereof:

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-E30 N-[(D)Lys]-[(D)NMeTyr]-NH₂ (SEQ ID NO:201 ),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu]-EN-[(D)His]-[(D)NMeTyr]-NH2 (SEQ 1DNO:202), h 158

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Orn]-[(D)NMeTyr]-NH₂ (SEQ ID NO:203),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Ser]-[(D)NMeTyr]-NH₂ (SEQ ID NO:204),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Phe]-[(D)NMeTyr]-NH₂ (SEQ ID NO:205),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-H-[(D)Tyr]-NH₂ (SEQ ID NO:206),

Ac-[Pen]-N-T-[W(7-Me)]-[(D)Tyr]-[Pen]-Phe[4-(2-aminoethoxy)H2-Nal]-[a-MeLys]10 [Lys(Ac)]-N-[(D)Lys]-[(D)NMeTyr]-NH₂ (SEQ ID NO:207),

Ac-[(D)Arg]-[Pen]-.N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-ammoethoxy)]-[2-Nal]-[THP]-EN-H-P-NH2 (SEQ ID NO:208),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-H-[(D)Pro]-NH₂ (SEQ ID NO:209),

Ac-[Pen]-N-T-[W(7-Me)]-[Phe(4-CONH2)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Lys]-[(D)NMeTyr]-NH₂ (SEQ ID NO:210),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc|-E-N(D)Phe[4-NH₂]-[Sarc]-NH2 (SEQ ID N0:211),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E20 N-H-NH2 (SEQ ID NO:212),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-N(H)Me (SEQ ID NO:213)_S

Ac-[Pen]-N-T-[W(7-Me)]-[Phe(4-NH(Ac))]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Lys]-[(D)NMeTyr]-NH₂ (SEQ ID NO:214),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)HPen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLysJ[Lys(Ac)]-N-[(D)Tyr]-[(D)NMeTyr]-NH₂ (SEQ IDNO:215),

Ac-[Pen]-N-T-[W(7-Me)]-(Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Na]]-[aMeLeu]-[Lys(Ac)]-NKD)LysH(D)NMeTyr]-NH₂ (SEQ ID NO:216),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]30 [Lys(Ac)]-N-[(D)HisH(D)NMeTyr]-NH₂ (SEQ ID NO:217),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nall-[a-MeLys][Lys(Ac)]-N-[bAla]-[(D)NMeTyr]-NH₂ (SEQ ID NO:218),

B 159

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[bAlaH(D)NMeTyr]-NH₂ (SEQ ID NO:219),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[bAIa]-[(D)NMeTyr]-NH₂ (SEQ ID NO:220),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-E-N-H-N(H)Me (SEQ IDNO:221),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[THP]-P-NH₂ (SEQ ID NO:222),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E10 N-[THP]-[(D)Pro]-NH₂ (SEQ ID NO:223),

Ac-[(D)Arg]-[Pen]~N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[bAla]-[Sarc]-NH₂ (SEQ ID NO:224),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[(D)Val]-[Sarc]-NH₂ (SEQ ID NO:225),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[(D)Arg]-[Sarc]-NH₂ (SEQ ID NO:226),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[Hph]-[Sarc]-NH₂ (SEQ ID NO:227),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe|4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-E-N-Phe[420 NH₂]-[Sarc]-NH₂ (SEQ ID NO:228),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-Phe[4-NH₂]-[Sarc]-NH₂ (SEQ ID NO:229),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-F-[Sarc]-NH₂ (SEQ ID NO:230),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-EN-[THP]-[Sarc]-NH₂ (SEQ ID NO:231 ),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Pbe[4-(2-ammoethoxy)]-[2-Nal]-[Acvc]-EN-[(D)Leu]-[Sarc]-NH₂ (SEQ ID NO:232),

Ac-[(D)Arg]-[Cys]-N-T-[W(7-Me)]-[Lys(Ac)]-[aMeCys]-Phe[4-(2-aminoethoxy)]-[2-Nal]30 [Acvc]-E-N-H-[Sarc]-NH₂ (SEQ ID NO:233),

Ac-[(D) Arg]-[Cys] -N-T-[W (7-Me)]-[Lys(Ac)]-[aMeCy s]-Phe[4-(2-ami noethoxy)]-[2-Nal] [Acvc]-E-N-[(D)Leu]-[Sarc]-NH₂ (SEQ ID NO:234),

B 160

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Na!]-[Acvc]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NO:235),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[bAla]-[Sarc]-NH₂ (SEQ ID NO:236),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Val]-[Sarc]-NH₂ (SEQ ID NO:237),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Arg]-[Sarc]-NH₂ (SEQ ID NO:238),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]10 [Lys(Ac)l-N-[Hph]-[Sarc]-NH2 (SEQ ID NO:239),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Tyr]-[Sarc]-NH₂ (SEQ ID NO;240),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[(D)Tyr]-[Sarc]-NH₂ (SEQ ID NO:241),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[4Pal]-NH₂ (SEQ ID NO:242),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[Phe(4-CF3)]-[Sarc]-NH₂ (SEQ ID NO:243),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]20 [Lys(Ac)]-N-Tyr_CHF2-[SarcJ-NH₂ (SEQ ID NO:244),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys|[Lys(Ac)]-N-[THP]-P-NH2 (SEQ ID NO:245),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-[(D)NMeTyr]-NH₂ (SEQ ID NO:246),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]'[THP]-EN-[3Pal]-[Sarc]-NH₂ (SEQ IDNO:247),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[4Pal]-[Sarc]-NEE (SEQ ID NO:248),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E30 N-[Phe(2-aminomethyl)]-[Sarc]-NH₂ (SEQ ID NO:249),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Pro(4,4diF)]-NH₂ (SEQ ID NO:250),

B I6l

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[aMePro]-NH₂ (SEQ ID NO:25 l),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-jPen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Aib]-NH₂ (SEQ ID NO:252),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[His(3-Me)]-[Sarc]-NH₂ (SEQ IDNO:253),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)J-[2-Nal]-[THP]-EN-[His(3-Me)]-[Sarc]-NH2 (SEQ ID NO:26l),

Ac-[(D)Arg]-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N10 [His(3-Me)]-[Sarc]-NH₂ (SEQ ID NO:262),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:266),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-N(H)Me (SEQ ID NO:267),

[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Pal]-[Sarc]-NH₂ (SEQ ID NO:270),

Ac-[(D)Arg]-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Pal]-[Sarc]-NH₂(SEQ IDNO:27l),

Pr-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-(N-propionylarnino)ethoxy)]-[220 Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO:272),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-(N-(4-hydroxy-3-methylphenyl) propionylamino) ethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO:273),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-NalHTHP]-EN-[3Pal(5-Me)]-[Sarc]-NH₂ (SEQ ID NO:276)_f

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal(5-NH2)]-[Sarc]-NH₂ (SEQ ID NO:277),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[His(3Me)]-N(H)Me (SEQ ID NO:278),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E30 N-[3Pal]-[(D)NMeTyr]-NH₂ (SEQ ID NO:279),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[G[y(N-cyclohexylmethyl)]-NH₂ (SEQ ID NO:280),

162

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THPJ-EN-[3Pa!]-[Gly(N-isobutyl)]-NH2 (SEQ ID NO:28l),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal(3-Me)]-NH₂ (SEQ ÏD NO:282),

Ac-[(D)Arg]-[aMeCys]-N-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:283),

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH2 (SEQ ID NO:284),

Ac'[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-E-N-[3Pal]-[Sarc]NH₂ (SEQ ID NO:285, 159),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH₂ (SEQ IDNO:286),

Ac-[Pen]-[Gly(Allyl)]-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Tyr(O-Allyl)]-[2-'Nal]-[THP]-[Lys(Ac)]N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:287),

Ac-[Pen]-[Gly(Allyl)]-D-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Tyr(O-Allyl)]-[2-Nal]-[THP]-[Lys(Ac)]N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO;288),

Ac-[Pen]-[Gly(AI]y])]-T-(W(4-F)]-[Lys(Ac)]-[Pen]-[Tyr(O-Allyl)]-[2-Nal]-[THP]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂ (SEQ ID NO:289),

Ac-[Pen]-N-D-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ ID NO:290),

Ac-[Pen]-L-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ IDNO:291),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH2 (SEQ IDNO:299),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-F-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:308),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[(D)Tyr]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pall·^

NH₂ (SEQ ID NO:309),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-(Pen]-[Phe(4-OMe)]-[2-Nal]-[THPHLys(Ac)]-N-[3Pal][Sarc]-NH₂ (SEQ ID NO:310),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-Nal]-[THP]-[Lys(Ac)]-N[3Pal]-[Sarc]-NH₂, (SEQ ID NO:31 i)

B 163

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(N-acetyl-N-propyl)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQ IDNO:332),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(N-acetyl-N-butyl)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:333),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(N-acetyl’N-isobuty!)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:334),

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(N-acetyl-N-benzyl)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[3Pa1]-[Sarc]-NH₂ (SEQ ID NO:335),

Ac-[Pen]-L-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-(Phe(4-CONH2)]-[2-Nal]-[a-MeLeu]-E-N-[3Pal]10 [Sarc]-NH₂ (SEQ ID NO:339),

Ac-[Pen]-L-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-OMe)]-[2-Nal]-[aMeLeu]-E-N-[3Pal]-[Sarc]NH₂ (SEQ ID NO:347), or

Ac-[Abu]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ ID NO :373), and wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond; or via an Abu-C thioether bond.

[00359] In certain related embodiments of methods of treating an IBD, ulcerative colitis or Crohn’s disease, the peptide inhibitor comprises or is any one of the amino acid sequence listed below; or a pharmaceutically acceptable sait thereof:

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ ID NO: 104),

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ IDNO:106),

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]25 NH₂ (SEQ ID NOs: 158, 162,284),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH₂(SEQ ID NOs:247, 266),

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[His(3-Me)]-[Sarc]-NH₂(SEQ ID NO:261), or

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-N(H)Me (SEQ IDNO:267), wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond.

164

[00360] In certain related embodiments of methods of treating an IBD, ulcerative colitis or Crohn s disease, the peptide inhibitor comprises or is any one of the amino acid sequence listed below; or a pharmaceutically acceptable sait thereof:

Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ ID NO: 104), wherein the peptide inhibitor is cyclized via a Pen-Pen disulfïde bond.

[00361] In certain related embodiments of methods of treating an IBD, ulcerative colitis or Crohn’s disease, the peptide inhibitor comprises or is any one of the amino acid sequence listed below; or a pharmaceutically acceptable sait thereof:

Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)H2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH₂ (SEQ IDNO:106), wherein the peptide inhibitor is cyclized via a Pen-Pen disulfïde bond.

[00362]In certain related embodiments of methods of treating an IBD, ulcerative colitis or Crohn’s disease, the peptide inhibitor comprises or is any one of the amino acid sequence listed below; or a pharmaceutically acceptable sait thereof:

Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]NH₂(SEQ IDNO:158), wherein the peptide inhibitor is cyclized via a Pen-Pen disulfïde bond.

[00363]In certain related embodiments of methods of treating an IBD, ulcerative colitis or Crohn’s disease, the peptide inhibitor comprises or is any one of the amino acid sequence listed below; or a pharmaceutically acceptable sait thereof:

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-(THP]-EN-[3Pal]-[Sarc]-NH₂ (SEQ ID NO:247), wherein the peptide inhibitor is cyclized via a Pen-Pen disulfïde bond.

[00364] In certain related embodiments of methods of treating an IBD, ulcerative colitis or Crohn’s disease, the peptide inhibitor comprises or is any one of the amino acid sequence listed below; or a pharmaceutically acceptable sait thereof:

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[TH.P]-EN-[His(3-Me)l-[Sarc]-NH₂ (SEQ ID NO:261), wherein the peptide inhibitor is cyclized via a Pen-Pen disulfïde bond.

[00365] In certain related embodiments of methods of treating an IBD, ulcerative colitis or Crohn’s disease, the peptide inhibitor comprises or is any one of the amino acid sequence listed below; or a pharmaceutically acceptable sait thereof:

165

Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-N(H)Me (SEQ ID NO:267), wherein the peptide inhibitor is cyclîzed via a Pen-Pen disulfide bond.

[00366] In certain related embodiments, the present invention provides a method of selectîvely inhibiting IL-23 or IL-23R signaling (or the binding of IL-23 to IL-23R) in a subject in need thereof, comprising providing to the subject a peptide inhibitor of the present invention. In particular embodiments, the present invention includes a method of selectîvely inhibiting IL-23 or IL-23R signaling (or the binding of IL-23 to IL-23R) in the GI tract of a subject in need thereof, comprising providing to the subject a peptide inhibitor of the present invention by oral administration. In particular embodiments, exposure of the adminîstered peptide inhibitor in G1 tîssues (e.g., small intestine or colon) is at least 10-fold, at least 20-fold, at least 50-fold, or at least I OO-fold greater than the exposure in the blood. In particular embodiments, the present invention includes a method of selectîvely inhibiting IL23 or 1L23R signaling (or the binding of IL23 to IL23R) in the GI tract of a subject in need thereof, comprising providing to the subject a peptide inhibitor, wherein the peptide inhibitor does not block the interaction betw een IL-6 and 1L-6R or antagonize the IL-12 signaling pathway. In a further related embodiment, the present invention includes a method of inhibiting GI inflammation and/or neutrophil infiltration to the GI, comprising providing to a subject in need thereof a peptide inhibitor of the present invention. In some embodiments, methods of the present invention comprise providing a peptide inhibitor of the present invention (i.e., a first therapeutic agent) to a subject in need thereof in combination with a second therapeutic agent. In certain embodiments, the second therapeutic agent is provided to the subject before and/or simultaneously with and/or after the peptide inhibitor is adminîstered to the subject. In particular embodiments, the second therapeutic agent is an anti-inflammatory agent. In certain embodiments, the second therapeutic agent is a non-steroidal anti-inflammatory drug, steroîd, or immune modulating agent. In certain embodiments, the method comprises administering to the subject a third therapeutic agent. In certain embodiments, the second therapeutic agent is an antibody that binds IL-23 or IL-23R.

PHARMACEUTICAL COMPOSITIONS

[00367] In particular embodiments, the peptide inhibitor, or the pharmaceutical composition comprising a peptide inhibitor, is suspended in a sustained-release matrix. A sustaîned-release matrix, as used herein, is a matrix made of materials, usually polymers, which are degradable by enzymatic or acid-base hydrolysis or by dissolution. Once inserted into the body, the matrix is acted upon by enzymes and body fluids. A sustained-release matrix desirably is chosen from

166 biocompatible materials such as liposomes, polylactides (polyiactic acid), poiyglycolide (polymer of glycolic acid), poiylactide co-glycolide (copolymers of lactic acid and giycolic acid) polyanhydrîdes, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholîpids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucîne, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone. One embodiment of a biodégradable matrix is a matrix of one of either poiylactide, poiyglycolide, or poiylactide co-glycolide (co-polymers of lactic acid and glycolic acid).

[00368] In certain embodiments, the présent invention includes pharmacetical compositions comprising one or more peptide inhibitors of the présent invention and a pharmaceutically acceptable carrier, diluent or excipient. A pharmaceutically acceptable carrier, diluent or excipient refers to a non-toxic solid, semi-solid or liquid fil 1er, diluent, encapsulating material or Formulation auxiliary of any type. Prévention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phénol sorbic acid, and the like. It may also be désirable to include isotonie agents such as sugars, sodium chloride, and the like.

[00369] In certain embodiments, the compositions are administered orally, parenterally, intracisternally, intravaginally, intraperitoneally, intrarectally, topically (as by powders, ointments, drops, suppository, or transdermal patch), by inhalation (such as intranasal spray), ocularly (such as intraocularly) or buccally. The term “parentéral” as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subeutaneous, intradermal and intraarticular injection and infusion. Accordingly, in certain embodiments, the compositions are Formulated for delivery by any of these routes of administration.

[00370] In certain embodiments, pharmaceutical compositions for parentéral injection comprise pharmaceutically acceptable stérile aqueous or nonaqueous solutions, dispersions, suspensions or émulsions, or stérile powders, for reconstitution into stérile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, éthanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, β-cyclodextrin, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluîdity may be maintained, for example, by the use of coatîng materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Thés compositions may also

167 contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersmg agents. Prolonged absorption of an injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.

[00371] Injectable depot forms include those made by forming microencapsule matrices of the peptide inhibitor in one or more biodégradable polymers such as polylactide-polyglycolide, poly(orthoesters), poly(anhydrîdes), and (poly)glycols, such as PEG. Depending upon the ratio of peptide to polymer and the nature of the particular polymer employed, the rate of release of the peptide inhibitor can be controlled. Depot injectable Formulations are also prepared by entrapping the peptide inhibitor in liposomes or microemulsions compatible with body tissues.

[00372] The injectable Formulations may be sterilized, for example, by filtration through a bacteri al-retain ing filter, or by incorporating sterilizing agents in the form of stérile solid compositions which can be dissolved or dispersed in stérile water or other stérile injectable medium just prior to use.

[00373]Topical administration includes administration to the skin or mucosa, including surfaces of the lung and eye. Compositions for topical lung administration, including those for inhalation and intranasal, may involve solutions and suspensions in aqueous and non-aqueous Formulations and can be prepared as a dry powder which may be pressurized or non-pressurized. In nonpressurized powder compositions, the active ingredientmay be finely divided form may be used in admixture with a larger-sized pharmaceutically acceptable inert carrier comprising particles having a size, for example, of up to 100 micrometers in diameter. Suitable inert carriers include sugars such as lactose.

[00374] Altematively, the composition may be pressurized and contain a compressed gas, such as nitrogen or a liquefied gas propellant. The liquefied propellant medium and indeed the total composition may bey such that the active ingrédient does not dissolve therein to any substantial extent. The pressurized composition may also contain a surface active agent, such as a liquid or solid non-ionic surface active agent or may be a solid anionic surface active agent. It is preferred to use the solid anionic surface active agent in the form of a sodium sait.

[00375] A further form of topical administration is to the eye. A peptide inhibitor of the invention may be delivered in a pharmaceutically acceptable ophthalmic vehîcle, such that the peptide inhibitor is maintained in contact with the ocular surface for a sufficient time period to allow the peptide inhibitor to penetrate the corneal and internai régions of the eye, as for example the anterîor chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/ciIiary, lens, choroid/retina and sciera. The pharmaceutically acceptable ophthalmic vehicle may, for

168 example, be an ointment, vegetable oil or an encapsulatîng material. Alternatively, the peptide inhibitors of the invention may be injected directly into the vitreous and aqueous humour.

[00376] Compositions for rectal or vaginal administration include suppositories which may be prepared by mixing the peptide inhibitorss of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at room température but liquid at body température and, therefore, melt in the rectum or vaginal cavity and release the active compound.

(00377] Peptide inhibitors of the présent invention may also be administered in liposomes or other lipid-based carriers. As is known in the art, liposomes are generally derived from phospholipîds or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The présent compositions in liposome form can contain, in addition to a peptide inhibitor of the présent invention, stabilizers, preservatîves, excipients, and the like. In certain embodiments, the lipids comprise phospholipîds, including the phosphatidyl cholines (lecithins) and serines, both natural and synthetic. Methods to form liposomes are known in the art.

[00378] Pharmaceutical compositions to be used in the invention suitable for parentéral administration may comprise stérile aqueous solutions and/or suspensions of the peptide inhibitos made isotonie with the blood of the récipient, generally using sodium chloride, glycerin, glucose, mannitol, sorbitol, and the like.

[00379]In some aspects, the invention provides a pharmaceutical composition for oral delivery. Compositions and peptide inhibitors of the instant invention may be prepared for oral administration according to any of the methods, techniques, and/or delivery vehicles described herein. Further, one having skill in the art will appreciate that the peptide inhibitors of the instant invention may be modified or integrated into a system or delivery vehicle that is not disclosed herein, yet is well known in the art and compatible for use in oral delivery of peptides.

[00380] In certain embodiments, Formulations for oral administration may comprise adjuvants (e.g. resorcinols and/or nonionic surfactants such as polyoxyethylene oleyl ether and nhexadecylpoiyethylene ether) to artificially increase the permeability of the intestinal walls, and/or enzymatic inhibitors (e.g. pancreatic trypsin inhibitors, diisopropyltluorophosphate (DFF) or trasylol) to inhibit enzymatic dégradation. In certain embodiments, the peptide inhibitor of a solidtype dosage form for oral administration can be mixed with at least one additive, such as sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextran, starches, agar, alginates, chitins,

169 chitosans, pectins, gum tragacanth, gum arable, gelatin, collagen, casein, albumm, synthetic or semisynthetic polymer, or glyceride. These dosage forms can also contain other type(s) of additives, e.g., inactive diluting agent, lubricant such as magnésium stéarate, paraben, preserving agent such as sorbic acid, ascorbic acid, alpha-tocopherol, antioxidants such as cysteine, disintegrators, binders, thickeners, buffering agents, pH adjusting agents, sweetening agents, flavoring agents or perfuming agents.

[00381] In particular embodiments, oral dosage forms or unit doses compatible for use with the peptide inhibitors of the present invention may include a mixture of peptide inhibitor and nondrug components or excipients, as well as other non-reusable materials that may be considered either as an ingrédient or packaging. Oral compositions may include at least one of a liquid, a solid, and a semi-solid dosage forms. In some embodiments, an oral dosage form is provided comprising an effective amount of peptide inhibitor, wherein the dosage form comprises at least one of a pill, a tablet, a capsule, a gel, a paste, a drink, a syrup, ointment, and suppository. In some instances, an oral dosage form is provided that is designed and configured to achîeve delayed release of the peptide inhibitor in the subject’s small intestine and/or colon.

[00382| In certain embodiments, an oral pharmaceutical composition comprising a peptide inhibitor of the present invention comprises an enteric coating that is designed to delay release of the peptide inhibitor in the small intestine. In at least some embodiments, a pharmaceutical composition is provided which comprises a peptide inhibitor of the present invention and a protease inhibitor, such as aprotinin, in a delayed release pharmaceutical Formulation. In some instances, pharmaceutical compositions of the instant invention comprise an enteric coat that is soluble in gastric juice at a pH of about 5.0 or higher. In at least one embodiment, a pharmaceutical composition îs provided comprising an enteric coating comprising a polymer having dissociable carboxylic groups, such as dérivatives of cellulose, including hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate and cellulose acetate trimellitate and similar dérivatives of cellulose and other carbohydrate polymers.

[00383]In certain embodiments, a pharmaceutical composition comprising a peptide inhibitor of the present invention is provided in an enteric coating, the enteric coating being designed to protect and release the pharmaceutical composition in a controlled manner within the subject’s lower gastrointestinal System, and to avoîd systemic side effects. In addition to enteric coatings, the peptide inhibitors of the instant invention may be encapsulated, coated, engaged or otherwise associated within any compatible oral drug delivery System or component. For example, in some embodiments a peptide inhibitor of the present invention is provided in a lipid carrier System

170 comprising at least one of polymeric hydrogels, nanoparticies, microspheres, micelles, and other lipid Systems.

[00384] To overcome peptide dégradation in the small intestine, some embodiments of the présent invention comprise a hydrogel polymer carrier system in which a peptide inhibitor of the présent invention is contained, whereby the hydrogel polymer protects the peptide inhibitor from proteolysis in the small intestine and/or colon. The peptide inhibitors of the présent invention may further be Formulated for compatible use with a carrier system that is desîgned to increase the dissolution kînetîcs and enhance intestinal absorption of the peptide. These methods include the use of liposomes, micelles and nanoparticies to increase GI tract perméation of peptides.

[00385] Various bioresponsive Systems may also be combined with one or more peptide inhibitor of the présent invention to provide a pharmaceutical agent for oral delivery. In some embodiments, a peptide inhibitor of the instant invention is used in combination with a bioresponsive system, such as hydrogels and mucoadhesive polymers with hydrogen bonding groups (e.g., PEG, poly(methacrylic) acid [PMAA], cellulose, Eudragit®, chitosan and alginate) to provide a therapeutîc agent for oral administration. Other embodiments include a method for optimizing or prolonging drug résidence time for a peptide inhibitor disclosed herein, wherein the surface of the peptide inhibitor surface is modified to comprise mucoadhesive properties through hydrogen bonds, polymers with linked mucins or/and hydrophobie interactions. These modified peptide molécules may demonstrate increase drug résidence time within the subject, in accordance with a desired feature of the invention. Moreover, targeted mucoadhesive Systems may specifically bind to receptors at the enterocytes and M-cell surfaces, thereby further increasing the uptake of particles containing the peptide inhibitor.

[00386] Other embodiments comprise a method for oral delivery of a peptide inhibitor of the présent invention, wherein the peptide inhibitor is provided to a subject in combination with perméation enhancers that promote the transport of the peptides across the intestinal mucosa by increasing paracelhilar or transcellular perméation. Various perméation enhancers and methods for the oral delivery of therapeutîc agents is described in Brayden, D.J., Mrsny, RJ., 2011. Oral peptide delivery: priorîtizing the leading technologies. Ther. Delivery 2(12), 1567-1573.

[00387] In certain embodiments, pharmaceutical compositions and Formulations of the présent invention comprises a peptide inhibitor of the présent invention and one or more perméation enhancer. Examples of absorption enhancers may include Bile salts, fatty acids, surfactants (anionic, cationic, and nonanionîc) chelators, Zonular OT, esters, cyclodextrin, dextran sulfate, azone, crown ethers, EDTA, sucrose esters, and phosphotidyl choline, for example. Although ] 71 absorption enhancers are not typically carriers by themselves, they are also widely associated with other carriers to improve oral bioavailability by transportîng of peptides and proteins across the intestinal mucosa. Such substances can be added to the Formulation as excipients or incorporated to form non spécifie interactions with the întended peptide inhibitor.

[00388] Dietary components and/or other naturally occurring substances affirmed as enhancing tight junctîon perméation and as Generally Recognîzed As Safe (GRAS) include, e.g., asglycerides, acylcarnitines, biie salts, and medium chain fatty acids. Sodium salts of medium chain fatty acids (MCFAS) were also suggested to be perméation enhancers. The most extensively studied MCFAS îs sodium caprate, a sait of capric acid, which comprises 2-3% of the fatty acids in the milk fat fraction. To date, sodium caprate îs mainly used as an excipient in a suppository Formulation (Doktac illin™) for împroving rectal ampicillîn absorption. The perméation properties of another dietary MCFAS, sodium caprylate (8-carbon), were shown in vitro to be Iower when compared to sodium caprate. Sodium caprylate and a peptidîc drug were Formulated in an admixture with other excipients in oil to generate an oily suspension (OS) that enhanced permeability (Tuvia, S. et al., Pharmaceutical Research, Vol. 31, No. 8, pp. 2010-2021 (2014).

[00389] For example, In certain embodiments, a perméation enhancer is combined with a peptide inhibitor, wherein the perméation enhancer comprises at least one of a medium-chain fatty acid, a long-chain fatty acid, a bile sait, an amphiphilic surfactant, and a chelating agent. In certain embodiments, medium-chain fatty acid salts promote absorption by increasing paracellular permeability of the intestinal epithelium. In certain embodiments, a perméation enhancer comprising sodium N-[hydroxybenzoyl)amino] caprylate is used to form a weak noncovalent association with the peptide inhibitor of the instant invention, wherein the perméation enhancer favors membrane transport and further dissociation once reaching the blood circulation. In certain embodiments, a peptide inhibitor ofthe présent invention is conjugated to oligoarginine, thereby increasing cellular pénétration of the peptide into various cell types. Further, in at least one embodiment a noncovalent bond is provided between a peptide inhibibitor ofthe présent invention and a perméation enhancer selected from the group consisting of a cyclodextrin (CD) and a dendrimers, wherein the perméation enhancer reduces peptide aggregation and increasing stability and solubility for the peptide inhibitor molécule.

[00390] In certain embodiments, a pharmaceutical composition or Formulation comprises a peptide inhibitor of the présent invention and a transient permeability enhancers (TPEs). Perméation enhancers and TPEs may be used to increase orally bioavailability or the peptide inhibitor. One example of a TPE that may be used is an oily suspension Formulation that disperses a powder

172 containîng sodioum caprylate and a therapeutic agent (Tuvia, S. et aL, Pharmaceutical Research, Vol. 31, No. 8, pp. 2010-2021 (2014).

[00391] In certain embodiments, pharmaceutical composition and Formulations may include a peptide inhibitor of the présent invention and one or more absorption enhancers, enzyme inhibitors, or mucoso adhesive polymers.

[00392] In particular embodiments, peptide inhibors of the présent invention are Formulated in a Formulation vehicle, such as, e.g., émulsions, liposomes, microsphere or nanoparticles.

[00393] Other embodiments of the invention provide a method for treating a subject with a peptide inhibitor of the présent invention having an increased half-life. In one aspect, the présent invention provides a peptide inhibitor having a half-life of at least several hours to one day in vitro or in vivo (e.g., when administered to a human subject) sufficient for daily (q.d.) or twice daily (b.i.d.) dosing of a therapeutically effective amount. In certain embodiments, the peptide inhibitor has a half-life of three days or longer sufficient for weekly (q.w.) dosing of a therapeutically effective amount. In certain embodiments, the peptide inhibitor has a half-life of eight days or longer sufficient for bi-weekly (b.i.w.) or monthly dosing of a therapeutically effective amount. In certain embodiments, the peptide inhibitor is derivatized or modified such that is has a longer half-life as compared to the underivatized or unmodified peptide inhibitor. In certain embodiments, the peptide inhibitor contains one or more Chemical modifications to increase sérum half-life.

[00394] When used in at least one of the treatments or delivery Systems described herein, a peptide inhibitor of the présent invention may be employed in pure form or, where such forms exist, in pharmaceutically acceptable sait form.

[00395] The total daily usage of the peptide inhibitors and compositions of the présent invention can be decided by the attending physicîan within the scope of sound medical judgment. The spécifie therapeutically effective dose level for any particular subject will dépend upon a varîety of factors including: a) the disorder being treated and the severity ofthe disorder; b) activity ofthe spécifie compound employed; c) the spécifie composition employed, the âge, body weight, general health, sex and diet of the patient; d) the time of administration, route of administration, and rate of excrétion of the spécifie peptide inhibitor employed; e) the duration of the treatment; f) drugs used in combination or coincidental with the spécifie peptide inhibitor employed, and like factors well known in the medical arts.

|00396] In particlar embodiments, the total daily dose of the peptide inhibitors of the invention to be administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.0001 to 300 mg/kg body weight daily or 1 to 300 mg/kg body weight daily.

173

NON-INVASIVE DETECTION OF INTESTINAL INFLAMMATION

[00397] The peptide inhibitors of the invention may be used for détection, assessment and diagnosïs of intestinal inflammation by microPET imaging, wherein the peptide inhibitor is labeled with a chelating group or a détectable label, as part of a a non-invasive diagnostic procedure. In certain embodiments, a peptide inhibitor is conjugated with a bifunctional chelator. In certain embodiments, a peptide inhibitor is radîolabeled. The labeled peptide inhibitor is then administered to a subject orally or rectally. In certain embodiments, the labeled peptide inhibitor is included in drinking water. Following uptake of the peptide inhibitor, microPET imaging may be used to vîsualize inflammation throughout the subject’s bowels and digestive track.

I EXAMPLES

SYNTHESIS OF SUBSTITUTED TRYPTOPHANS

Synthesis of 7-methyl tryptophan

[00398] 7-Methyl tryptophan was purchased from a commercial source. Additionally, the compound can be synthesized following one of the methods described below.

Synthesis of 7-ethyl tryptophan

[00399] 7-Ethyl tryptophan was synthesized following the method depicted in Scheme l :

Scheme l

Synthesis of 7-ispropvl tryptophan

[00400] 7-Isopropyl tryptophan was synthesized following the method depicted in Scheme 2;

174

Scheme 2

1. NaOMe

2. TFA

Fmoc-OSu

Procedures for 7-isopropyl compound:

Suzuki Coupling:

[00401] To a solution of (S)-methyl 3-(7-bromo-lH-indol-3-yl)-2-((tert-butoxycarbonyI) amino) propanoate (5,0 g, 12.6 mmol) in n-propanol in sealed was added Ptassium isoprenyltrifluoroborate (2.2 g, 15.1 mmol) and was purged with nitrogen. To the above mixture was added triethylamine (3.5 mL, 25.5 mmol) and then the cataiyst [l,l'-Bis(diphenylphosphino)ferrocene]dich]oropalladiüm(l]), complex with 10 dichloromethane (0.72 g, 0.88 mmol), purged with nitrogen for 10 minutes and heated to 100 °C o verni ght.

The solution was concentrated to residue which was dissolved in ethyl acetate ( 150 mL) washed with water and brine. The organic layer was concentrated and crude was purified by flash column (3.2 g, 71%) to get thick foamy solid.

Transfer Hydrogénation:

[00402]To a solution of (S)-methyl 2-((tert-butoxycarbonyl) amino)-3-(7-(prop-l-en-2-yl)-lHindol-3-yl)propanoate (3.1 g, 8.6 mmol) in éthanol (40 mL) was added 10% Pd/C (100 mg, 50% wet cataiyst) and then was added ammonium formate (1.6 g, 25.3 mmol) and the resulting mixture was heated to 65- 70 °C, over 2 h. The reaction mixture was concentrated and water was added to the residue and extracted into ethyl acetate (2 x 100 mL). The organic layer was washed with water and brine and concentrated. The product (3.1 g, quantitative) obtained was used as such for the next réaction.

Hydrolysis:

[00403] To a solution of (S)-methyl 2-((tert-butoxycarbonyl) amino)-3-(7-isopropyl-lH-indol-3yl)propanoate (3.6 g, 10.0 mmol) in THF/MeOH/water (4:1:1) was added lithium hydroxide (1.26 25 g, 30.0 mmol) and the solution was stirred overnight. The solution was concentrated to remove

175 solvents and diluted with water and was acidified with 10% aqueous citnc acid. The water layer containing product was extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with water and brine, dried over Na2SO4 and concentrated to the desîred product (2.8 g, 94%) as thick oil. Crude taken into next step without further purification

B oc deprotection:

[00404] To a cold solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(7-îsopropyl-lH-indol-3yl)propanoic acid (2.8 g, 8.0 mmol) in dîchloromethane (12 mL) was added Trifluoroacetic acid (6 mL) and the solution was stirred for 5 h at room température. The solution was evaporated to dryness re-dîssolved in dîchloromethane (10 mL) was treated with HCl/ether to and concentrated. The crude hydrochloride sait was suspended in MTBE (25 mL), stirred for 30 minutes and fïltered to get S)-2-amino-3-(7-isopropyl-lH-indol-3-yl)propanoic acid hydrochloride (1.3 g, 68%) off white solid (hygroscopîc)

Fmoc protection:

[00405] To a solution of (S)-2-amino-3-(7-îsopropyl-lH-indol-3-yi)propanoic acid hydrochloride (1.3 g, 4.6 mmol) in THF/ water (33 mL: 10 mL) was added sodium bicarbonate (1.55 g, 18.4 mmol) and then N-(9-Fluorenylmethoxycarbonyloxy)succinîmide (1.55 g, 4.6 mmol) in portions. The resulting mixture was stirred overnight and concentrated to remove THF. The residue was diluted with water and was acidified with 2N HCl and extracted with ethyl acetate (2 x 75 mL). The organic layer was washed with water and brine, dried over Na₂SÛ4 and concentrated to get the product as a foamy low melting solid (1.85 g, 86%).

Synthesis of 7-phenvl substituted tryptophans

[00406] 7-Phenyl substituted tryptophan were or can be synthesîzed following the method depicted in Scheme 3:

I76

Scheme 3. 7-Phenyl Substituted Tryptophans

COOCH₃

1. NaOMe

2. TFA

Suzuki Coupling with Aryl Boronic acid

[00407] (S)-m ethyl 3-(7-bromo-lH-indol-3-yl)-2-((tert-butoxycarbonyl)amino)propanoate (4.0 g,

10.0 mmol) in dry toluene (30 mL) was purged for 10 min with nitrogen. K2CO3 (2.0 g, 15.0 mmol) in 10 mL ofwater was added followed by Phenyl boronic acid (1.47 g, 12.0 mmol) and the reaction mixture was purged for 10 min with nitrogen. Pd(dppf)Cb.DCM (0.58 g, 0.71 mmol), éthanol (10 mL) and THF (20 mL) were added and the reaction mixture was heated to 100 °C with stirring for

8 hr. The reaction mixture was concentrated under vacuum and the residue was dissolved in DCM (200 mL). The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by 60-120-mesh silica gel column chromatography to yieid the product (3.6 g ,90%) as foamy solid.

Hydrolysis:

[00408]To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(7-phenyl-lH-indol-3yl)propanoate (3.6 g, 9.1 mmol) in THF/MeOH/water (4:1:1) was added lithium hydroxide (1.15g, 27.3 mmol) and the solution was stirred ovemight. The solution was concentrated to remove solvents and diluted with enough water and was acidified with 10% citric acid. The water layer containing product was extracted with ethyl acetate (2x10 mL). The organic layer was washed with water and brine, dried over Na2SO4 and concentrated to the desired product (3.3 g, 95 %).

Boc Deprotection:

[00409] To an ice cooled solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(7-phenyl-lH-indol-3yl)propanoic acid (3.3 g, 8.6 mmol) in dîchlorometbane (13 mL) was added Trîfluoroacetic acid

177 (6.6 mL) and the solution was stirred for 6 h at room température. The solution was evaporated to dryness re-dissolved in dichloromethane (10 mL) was treated with HCI/ether to and concentrated. The crude hydrochloride sait was suspended in MTBE (25 mL), stirred for 30 minutes and filtered to get (S)-2-amino-3-(7-phenyl-lH-indol-3-yl)propanoic acid hydrochloride (1.8 g, 66 %).

Fmoc protection;

[00410] To a solution of (S)-2-amîno-3-(7-phenyl-lH-indol-3-yl)propanoic acid hydrochloride (1.8 g, 5.7 mmol) in THF/ water (45 mL: 13 mL) was added sodium bicarbonate (1.92 g, 22.8 mmol) and then N-(9-Fluorenylmethoxycarbonyloxy)succinimide (1.92 g, 5.7 mmol) in portions. The resulting mixture was stirred ovemight and concentrated to remove THF. The residue was diluted with enough water and was acidified with 2N HCl and extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with water and brine, dried over NajSCh and concentrated and residue was suspended in 20% MTBE/hexanes to yield the desired product (2.6 g. 92 %).

Synthesis of 7-heteroaryl substituted tryptophans

[00411] 7-Heteroaryl substituted tryptophan were or can be synthesized following the method depicted in Scheme 4;

Scheme 4. 7-Heteroaryl Substituted Tryptophans

R-B(OH)₃

Pd(dppf)CI₂

1. NaOMe

2. TFA

Fmoc-OSu

wherein R is heteroaryl, unsubstituted or substituted with halo, halo, alkyl, cyano, haloalkyl, hydroxy, or alkoxy.

[00412] Spécifie représentative R groups are selected from thienyl, pyridyl, piperidinyl, and morpholinyl.

178

Synthesis of 7-thienyl (thiophenyl) substituted tryptophans

[00413| 7-Thienyl (thîophenyl) substituted tryptophan were or can be synthesized following the method depicted in Scheme 5:

Scheme 5. 7-Thiophenyl Substituted Tryptophans

[00414] Suzuki-Miyaura cross-coupling reaction was performed using the modified approach described by Frese et al. (ChemCatChem 2016, 8, 1799-1803). Using the Na₂PdC14 as a Pd source in combination with the Buchwald ligand SPhos. This System îs known to catalyze challengîng substrate combinations with excellent results even at low températures. In our case the SuzukiMiyaura cross-coupling reaction of 7 bromoTrp and the boronic acid afforded the wanted product which we subsequently protected using Fmoc-OSu.

[00415] L-7-(Thîophen-3-yl)-tryptophan: 7-Bromo-L-tryptophan (0.283 g , 1 mmol), Thiophene3-boronic acid acid (0.383 g, 3.00 mmol, 3 equiv.) and K2CO3 (10 equiv.) were placed in a flask and purged with N2. Degassed water: 1-butanol (9:1, 30 mL) was added via a syringe, and the reaction was stirred at 95 °C. To initiate the reaction SPhos (6.2 mg, 15 mole %) and Na₂CLPd (15.2 mg, 5 mole %) were transferred to the mixture after previous warming of Pd sait and ligand for 10 min at 40 °C.

[00416] Upon completion, the aqueous reaction was diluted with H2O (20 mL) and the solution was acidîfied to pH 1.0 by dropwise addition of 1 M I-IC1. Precipitated palladium black was removed by filtration (Whatrnan, 20 gm pore size) and the fîltrate was lyophilized. Finally, the resulting crude product was purified by means of préparative reverse-phase high performance liquid chromatography (RP-HPLC) with a C18 column (5gm , 250 x 50 mm) with a flow rate of 50 mL/min. Séparation was achieved using linear gradients of buffer B in A (Buffer A : Aqueous 0.05% TFA; Buffer B: 0.043% TFA, 90% acetonitrile in water). Analysis was monîtored performed using a Cl8 column (3pm, 50 x 2mm) with a flow rate of 1 mL/min. Fractions containing pure product were then freeze-dried on a lyophilizer. Yield 104 mg (36% yield). MS (ESI) m/z 287.08 [M+H] + (Calcd. For CuHisChNS 287.12).

179

[00417] Fmoc-L-7-(Thiophen-3-yl)-tryptophan: The amino acid, L-7-(Thiophen-3-yl)-tryptophan (31.5 mg, 0.11 mmol) was dissolved in water and sodium bicarbonate (2 eq) with stirring. The resulting solution was cooled to 5° C and Fmoc-OSu (44.53 mg, 1.05 eq) added slowly as a solution in dioxane. The resulting mixture is stirred at 0° for 1 h and allowed to wann ovemight to room température. Water was then added and the aqueous layer is extracted 2 times with EtOAc. The organic layer was back extracted twice with saturated sodium bicarbonate solution. The combined aqueous layers are acidified to a pH of 1.0 with 10% HCl, and then extracted 3 times with EtOAc. The combined organic layers are dried (sodium sulfate) and concentrated în vacuo. The resulting residue was be purified by flash chromatography (SiO2) using (toluene, ethyl acteate, (1:1), 1% acetic acid). Yield 50 mg (89% yield). MS (ESI) niiz 509.10 [M+H] %Calcd. For C15H15O2NS 508.59).

Synthesis of additional 7-substîtuted tryptophans

[00418] Additional 7-substituted tryptophan were or can be synthesized followîng the method depicted in Scheme 3:

Additional 7-Substîtuted Tryptophans

h₃o⁺

R= OH, OMe, orCF₃

EXAMPLE 1 : SYNTHESIS OF PEPTIDE MONOMERS

[00419] Peptide monomers of the present invention were synthesized using the Merrifield solid phase synthesis techniques on Protein Technology’s Symphony multiple channel synthesizer. The peptides were assembled using HBTU (O-Benzotriazole-N,N,N’,N’-tetramethyl-uroniumhexafluoro-phosphate), Diisopropylethylamine(DIEA) coupling conditions. For some amino acid

180 couplings PyAOP(7-Azabenzotriazol- l-yloxy)tripyrrolidinophosponium bexafluorophosphate) and D1EA conditions were used. Rmk Amide MBHA resin (100-200 mesh, 0.57 mmo!/g) was used for peptide with C-terminal amides and pre-loaded Wang Resin with Ν-α-Fmoc protected amino acid was used for peptide with C-terminal acids. The coupling reagents (HBTU and D1EA premixed) were prepared at lOOmmo! concentration. Similarly amino acids solutions were prepared at 100 mmol concentration. Peptide inhibitors of the présent invention were îdentifîed based on medical chemistry optimization and/or phage display and screened to identify those having superîor binding and/or inhibitory propertîes.

Assembly

[00420] The peptides were assembled using standard Symphony protocols.The peptide sequences were assembled as follows; Resin (250 mg, 0.14 mmol) in each reaction vial was washed twice with 4mI of DMF followed by treatment with 2.5ml of 20% 4-methyl piperîdine (Fmoc deprotection) for 10min. The resin was then fdtered and washed two times with DMF (4ml) and retreated with N-methyl piperifine for additîonal 30 minute. The resin was again washed three times with DMF (4 ml) followed by addition 2.5ml of amino acid and 2.5ml of HBTU-DIEA mixture. After 45min of frequent agitations, the resin was filtered and washed three timed with DMF (4 ml each). For a typîcal peptide of the présent invention, double couplings were performed. After completing the coupling reaction, the resin was washed three times with DMF (4 ml each) before proceeding to the next amino acid coupling.

Ring Closing Metathesis to form Olefms

[00421]The resin (100 pmol) was washed with 2 ml of DCM (3 x 1 min) and then with 2 ml of DCE (3 x l min) before being treated with a solution of 2 ml of a 6 mM solution of Grubbs' fîrstgeneration catalyst in DCE (4.94 mg ml-1; 20 mol% with regard to the resin substitution). The solution was refluxed ovemight (12 h) under nitrogenbefore being drained. The resin was washed three times with DMF (4 ml each); DCM (4 ml) before being dried and cleavaed.

Cleavage

[00422] Following completion of the peptide assembly, the peptide was cleaved from the resin by treatment with cleavage reagent, such as reagent K (82.5% trigluoroacetic acid, 5% water, 5% thioanisole, 5% phénol, 2.5% 1,2-ethanedithiol). The cleavage reagent was able to successfully cleave the peptide from the resin, as well as ail remaining side chain protecting groups.

[00423] The cleaved peptides were precipitated in cold diethyl ether followed by two washings with ethyl ether. The fîltrate was poured off and a second aliquot of cold ether was added, and the procedure repeated. The crude peptide was dissolved in a solution of acetonitrîle: water (7:3 with

181

1% TFA) and filtered. The quahty of linear peptide was then ventied using electrospray lonization mass spectrometry (ESI-MS) (Micromass/Waters ZQ) before being purified.

Disulfïde Bond Formation via Oxidation

[00424] The peptide containing the free thiol (for example diPen) was assembled on a Rink AmideMBHA resin following general Fmoc-SPPS procedure. The peptide was cleaved from the resin by treatment with cleavage reagent 90% trifluoroacetic acid, 5% water, 2.5% 1,2-ethanedithiol, 2.5% tri-isopropylsilane). The cleaved peptides were precipitated in cold diethyl ether followed by two washings with ethyl ether. The filtrate was poured off and a second aliquot of cold ether was added, and the procedure repeated. The crude peptide was dissolved in a solution of acetonitrile; water (7:3 with 1% TFA) and filtered givîng the wanted unoxidized peptide crude peptide.

[00425] The crude, cleaved peptide with X4 and X9 possessing either Cys, Pen, hCys, (D)Pen, (D)Cys or (D)hCys, was dissolved în 20ml of water : acetonitrile. Saturated lodine in acetic acid was then added drop wise with stirring until yellow color persîsted. The solution was stirred for 15 minutes, and the reaction was monitored with analytic HPLC and LCMS. When the reaction was completed, solid ascorbic acid was added until the solution became clear. The solvent mixture was then purified by first being diluted with water and then loaded onto a reverse phase HPLC machine (Luna C18 support, lûu, Ι00Α, Mobile phase A: water containing 0.1% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1% TFA, gradient began with 5% B, and changed to 50% B over 60 minutes at a flow rate of 15ml/min). Fractions containing pure product were then freeze-dried on a lyophilyzer.

Thioether Bond Formation

[00426] The peptide containing the free thiol (e.g., Cys) and hSer(OTBDMS) was assembled on a Rink Amide-MBHA resin following general Fmoc-SPPS procedure. Chlorination was carried out by treating the resin with PPha (10 equiv.) and ChCCN (10 equiv.) in DCM for 2 h. The peptide was cleaved from the resin by treatment with cleavage reagent 90% trifluoroacetic acid, 5% water, 2.5% 1,2-ethanedithiol, 2.5% tri-isopropylsilane). The cleaved peptides were precipitated in cold diethyl ether followed by two washings with ethyl ether. The filtrate was poured off and a second aliquot of cold ether was added, and the procedure repeated. The crude peptide was dissolved in a solution of acetonitrile:water (7:3 with 1% TFA) and filtered giving the wanted uncyclized crude peptide.

[00427] The crude peptide possessing a free thiol (eg Cys, Pen, hCys, (D)Pen, (D)Cys or (D)hCys and the alkyl halide (hSer(CI)) at either the X4 and X9 position or X9 and X4 position was dissolved in 0.1 M TRIS buffer pH 8.5. Cyclization was allowed to take place ovemight at RT.

182

The solvent mixture was then purified by first being diluted two-fold with water and then loaded onto a reverse phase HPLC machine (Luna Cl8 support, lOu, Ι00Α, Mobile phase A: water containing 0.1% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1% TFA, gradient began with 5% B, and changed to 50% B over 60 minutes at a flow rate of 15ml/min). Fractions containing pure product were then freeze-dried on a lyophiiyzer.

Purification

[00428] Analytical reverse-phase, high performance liquid chromatography (HPLC) was performed on a Gemini C18 column (4.6 mm x 250 mm) (Phenomenex). Semi-Preparative reverse phase HPLC was performed on a Gemini 10 pm Cl 8 column (22 mm x 250 mm) (Phenomenex) or Jupiter 10 pm, 300 A ⁰ C18 column (21.2 mm x 250 mm)I (Phenomenex). Séparations were achieved using linear gradients of buffer B in A (Mobile phase A: water containing 0.15% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1 % TFA), at a flow rate of 1 mL/min (analytical) and 15 mL/mîn (préparative). Séparations were achieved using linear gradients of buffer B in A (Mobile phase A: water containing 0.15% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1 % TFA), at a flow rate of 1 mL/min (analytical) and 15mL/min (préparative).

EXAMPLE IA: ADDITIONAL REPRESENTATIVE SYNTHESIS OF PEPTIDE

MONOMERS

[00429] Peptide monomers of the present invention were synthesîzed using standard Fmoc solid phase synthesis techniques on a CEM Liberty Blue™ microwave peptide synthesizer. The peptides were assembled using Oxyma/DIC (ethyl cyanohydroxyiminoacetate/diisopropylcarbodiimide) with microwave heatîng. Rink Amide-MBHA resin (100-200 mesh, 0.66 mmol/g) was used for peptides with C-ten'ninal amides and pre-loaded Wang Resin with Ν-α-Fmoc protected amino acid was used for peptide with C-terminal acids. Oxyma was prepared as a ! M solution in DM F with 0.1M DIEA. DIC was prepared as 0.5M solution in DMF. The Amino acids were prepared at 200mM. Peptide inhibitors ofthe present invention were îdentified based on médicinal chemistry optimization and/or phage display and screened to identity those having superior binding and/or inhibitory properties.

Assembly

[00430] The peptides were made using standard CEM Liberty Blue™ protocols. The peptide sequences were assembled as follows: Resin (400 mg, 0.25 mmol) was suspended in 10 ml of 50/50 DMF/DCM. The resin was then transferred to the reaction vessel in the microwave cavity. The peptide was assembled using repeated Fmoc deprotection and Oxyma/DIC coupling cycles. For deprotection, 20% 4-methylpiperidîne in DMF was added to the reaction vessel and heated to

183 °C for 65 seconds. The deprotection solution was drained and the resin washed three times with DMF. For most amino acids, 5 équivalents of amino acid, Oxyma and DIC were then added to the reaction vessel and micro wave irradiation rapidly heated the mixing reaction to 90 °C for 4 mîn. For Arginine and Histidine residues, miider conditions using respective températures of 75 and 50 °C for 10 min were used to prevent racemization. Rare and expensive amino acids were often coupled manually ovemight at room température using only 1.5-2 eq of reagents. Difficult couplings were often double coupled 2x4 min at 90 °C. After coupling the resin was washed with DMF and the whole cycle was repeated until the desired peptide assembly was completed.

Ring Closing Metathesis to form Olefins

[00431]The resin (100 pmol) was washed with 2 ml of DCM (3 * l min) and then with 2 ml of DCE (3 ^χ l min) before being treated with a solution of 2 ml of a 6 mM solution of Grubbs Catalyst® l^st Génération in DCE (4.94 mg mF¹; 20 mol% with regard to the resin substitution). The solution was refluxed ovemight (12 h) under nitrogen before being drained. The resin was washed three times with DMF (4 ml each); DCM (4 ml) before being dried and cleaved.

Cleavage

[00432] Following completion ofthe peptide assembly, the peptide was then cleaved from the resin by treatment with a standard cleavage cocktail of 91:5:2:2 TFA/H2O/TIPS/DODT for 2 hrs. If more than one Arg(pbf) residue was présent the cleavage was allowed to go for an additional hour. [00433] The cleaved peptides were precipitated in cold diethyl ether. The filtrate was decanted oft and a second aliquot of cold ether was added, and the procedure was repeated. The qualîty of linear peptide was then verified using electrospray ionizatîon mass spectrometry (ESI-MS) (Waters® Micromass® ZQ™) before being purified.

Disulfide Bond Formation via Oxidation

[00434] The peptide containing the free thiol (for example diPen) was assembled on a Rink AmideMBHA resin following general Fmoc solid phase synthesis, cleavage and isolation as described above.

[00435] The crude, cleaved thiol containing peptide possessing either Cys, Pen, hCys, (D)Pen, (D)Cys or (D)hCys, was dissolved ~2mg/ml in 50/50 acetonitrile/water. Saturated iodine in acetic acid was then added dropwise with stirring until yellow color persîsted. The solution was stirred for a few minutes, and the reaction was monitored with analytic HPLC and LCMS. When the réaction was completed, solid ascorbîc acid was added until the solution became clear. The solvent mixture was then purified by first being diluted with water and then loaded onto a reverse phase HPLC Column (Luna® Cl8 support, lOu, 100A, Mobile phase A: water containing 0.1% TFA,

184 mobile phase B: acetonitrile (ACN) containing 0.1% TFA, gradient began with 15% B, and changed to 50% B over 60 minutes at a flow rate of 15ml/min). Fractions containing pure product were then freeze-dried on a lyophilizer.

Thioether Bond Formation

[00436] The peptide containing the free thiol (e.g., Cys) and hSer(OTBDMS) was assembled on a Rink Amide-MBHA resin following general Fmoc-SPPS procedure. Chlorination was carried out by treating the resin with Dichlorotriphenylphosphorane (5 eq, 0.5M) with Pinene (0.875M) and thioanisole (0.375M) scavengers at room température for 2 hours. The chloro-peptides were cleaved from the resin and precipitated as described above.

[00437] The crude peptide possessing a free thiol (e.g. Cys, Pen, hCys, (D)Pen, (D)Cys or (D)hCys and the alkyl halide (hSer(CI)) were dissolved in 1:1 ACN/water and diluted with one volume of 0.2 M TRIS buffer pH 8.4. Cyclization was performed ovemight at room température. The reaction mixture was then purified by first being diluted Ix with water and then loaded onto a reverse phase HPLC column (Luna® C18 support, lOu, 100A, Mobile phase A: water containing 0.1% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1% TFA, gradient began at 15% B, and changed to 50% B over 60 minutes at a flow rate of 20 ml/min). Fractions containing pure product as determined by RPHPLC were then freeze-dried on a lyophilizer.

Purification

[00438]Analytical reverse-phase, high performance liquid chromatography (HPLC) was performed on a Gemini® Cl8 column (4.6 mm x 250 mm) (Phenomenex). Semi-Preparative reverse phase FIPLC was performed on a Gemini® 10 pm Cl8 column (22 mm x 250 mm) (Phenomenex) or Jupiter® 10 pm, 300 A ⁰ C18 column (21.2 mm x 250 mm) (Phenomenex). Séparations were achieved using linear gradients of buffer B in A (Mobile phase A: water containing 0.15% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1% TFA), at a flow rate of 1 mL/min (analytical) and 20 mL/min (préparative).

EXAMPLE IB: ADDITIONAL REPRESENTATIVE SYNTHESIS OF PEPTIDE MONOMERS - SYNTHESIS OF PEPTIDE Ac-[Penl*-N-T-[W(7-Me)l-[Lys(Ac)1-rPen1*PheI4-(2-aminoethoxv)1-[2-Nal1-|THPl-E-N-r3-Pal]-Sarc-NH2 (*PEN-PEN FORM DISULFIDE BOND) (SEP. ÎD. NO. 104) (PEPTIDE # 104)

[00439]The synthesis of Peptide #104 is prepared using FMOC solid phase peptide synthesis techniques.

[00440] The Peptide #104 is constructed on Rink Amide MBFIA resin using standard FMOC protection synthesis conditions reported in the literature. The constructed peptide is isolated from

185 the res in and protectîng groups by cleavage with strong acid followed by précipitation. Oxidation to form the disulfide bond is performed followed by purification by RPHPLC and counterion exchange. Lyophîlization of pure fractions gives the final product Peptide #67.

[00441] Swell Resin: 10 g of Rink Amide MBHA solid phase resin (0.66mmol/g loading) is transferred to a 250 ml peptide vessel with filter frit, ground glass joint and vacuum side arm. The resin is washed 3x with DMF.

[00442] Step I : Coupling of FMOC-Sarc-OH: Deprotection of the resin bound FMOC group is realized by adding 2 resin-bed volumes of 20% 4-methyl-piperîdine in DMF to the swollen resin and shaking for 3-5 min prior to draining and adding a second, 2-resin-bed volume ofthe 4-methyl piperîdine solution and shaking for an additional 20-30 min. After deprotection the resin is washed 3x DMF with shaking. FMOC-Sarc-OH (3 eq, 6.2 g) is dissolved in 100 ml DMF along with Oxyma (4.5 eq, 4.22g). Preactivation of the acid is accomplîshed by addition of DIC (3.9 eq, 4 ml) with shaking for 15 min prior to addition to the deprotected resin. An additional alîquot of DIC (2.6 eq, 2.65 ml) is then added after ~ 15 min of coupling. The progress of the coupling réaction is monitored by the colorimétrie Kaiser test. Once the reaction is judged complété the resin is washed 3 x DMF with shaking prior to starting the next deprotection/coupling cycle.

[00443] Step 2: Coupling of FMOC-3Pal-OH: FMOC deprotection is again accomplîshed by adding two sequential, 2-resin-bed volumes of 20% 4-methyl-piperidine in DMF, one times 3-5 minutes and one times 20-30 minutes, draining in between treatments. The resin is then washed 3 times prior to coupling with protected 3-pyridyl alanine (3Pal). FMOC-3Pal-OH (3 eq, 7.8g) is dissolved in DMF along with Oxyma (4.5eq, 4.22g). Preactivation with DIC (3.9 eq, 4 ml) for 15 minutes is done prior to addition to the Sarc-Amide resin. After 15 minutes, an additional aliquot of DIC (2.6 eq, 2.65 ml) is added to the reaction. Once the reaction is complété as determined by the Kaiser test, the resin is again washed 3x with DMF prior to starting the next deprotection/coupling cycle.

[00444] Step 3: Coupling of FMOC-Asn(Trt)-OH: The FMOC is removed from the N-terminus of the resin bound 3Pal and washed as prevtously described. FMOC-Asn(Trt)-OH (2eq, 8g) is dissolved in 100ml of DMF along with Oxyma (3eq, 2.81g). DIC (2.6 eq, 2.65 ml) is added for preactivation of the acid for -15 minutes prior to addition to the 3Pal-Sarc-Amide resin. After -15 minutes, an additional aliquot of DIC (1.4 eq, 1.43 ml) is added to the reaction. Once the reaction is complété as determined by the Kaiser test, the resin is washed 3x with DMF prior to starting the next deprotection/coupling cycle.

186

[00445] Step 4: Coupling of FMOC-Glu(OtBu)-OH: The FMOC is removed from the N-termmus of the resin bound Asparigine and the resin washed with DMF as previously described. FMOCGlu(OtBu)-OH (2 eq, 5.91 g) is dissolved in 100ml of DMF along with Oxyma (3eq, 2.81g). D1C (2.6 eq, 2.65 ml) is added forpreactivation of the acid ~15 minutes prior to addition to the Asn(Trt)3Pal-Sarc-Amîde resin. After-15 minutes, an additional aliquot ofDIC (1.4 eq, 1.43 ml) is added to the reaction. Once the reaction is complété as determined by the Kaiser test the resin is washed 3x with DMF prior to starting the next deprotectîon/coupling cycle.

[00446] Step 5: Coupling of FMOC-THP-OH: The FMOC is removed from the N-terminus of the resin bound peptide and the resin is washed as previously described. FMOC-THP-OH (3 eq, 7.36 g) is dissolved in 100ml of DMF along with Oxyma (4.5 eq, 4.22g). DÏC (3.9 eq, 4 ml) is added for preactivation of the acid -15 minutes prior to addition to the Glu(OtBu)-Asn(Trt)-3Pal-SarcAmide resin. After -15 minutes, an additional aliquot of DIC (2.6 eq, 2.65 ml) is added to the reaction. Once the reaction is complété as determined by the Kaiser test the resin is washed 3x with DMF prior to starting the next deprotectîon/coupling cycle.

[00447] Step 6: Coupling of FMOC-L-Ala(2-Naphthyl)-OH (Nal): The FMOC is removed from the N-terminus of the resin bound peptide and the resin washed as previously described. FMOCL-Ala(2-Naphthyl)-OH (3 eq, 8.66 g) is dissolved in 100ml of DMF along with Oxyma (4.5 eq, 4.22g). DIC (3.9 eq, 4 ml) is added for preactivation of the acid -15 minutes prior to addition to the THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-Amide resin. After-15 minutes, an additional aliquot of DIC (2.6 eq, 2.65 ml) is added. Once the reaction is complété as determined by the Kaiser test the resin was again washed 3x with DMF prior to starting the next deprotectîon/coupling cycle.

[00448] Step 7: Coupling of FMOC-4-[2-(Boc-amino-ethoxy)]-L-Phenylalanine (FMOC-AEF): The FMOC is removed from the N-terminus of the resin bound peptide and the resin washed as previously described. FMOC-4-[2-(Boc-amino-ethoxy)]-L-Phenylalanîne (3 eq, 10.8 g) is dissolved in 100ml of DMF along with Oxyma (4.5 eq, 4.22g). DIC (3.9 eq, 4 ml) is added for preactivation of the acid -15 minutes prior to addition to the Nal-THP- Glu(OtBu)-Asn(Trt)-3PalSarc-Amide resin. After -15 minutes, an additional aliquot of DIC (2.6 eq, 2.65 ml) is added to the reaction. Once the reaction is complété as determined by the Kaiser test the resin is washed 3x with DMF prior to starting the next deprotectîon/coupling cycle.

[00449] Step 8: Coupling of FMOC-Pen(Trt)-OH : The FMOC is removed from the N-terminus of the resin bound peptide and the resin washed as previously described. FMOC-Pen(Trt)-OH (3 eq, 12.14 g) is dissolved in 100ml of DMF along with Oxyma (4.5 eq, 4.22g). DIC (3.9 eq, 4 ml) îs added for preactivation of the acid -15 minutes prior to addition to the AEF-Nal-THP-Glu(OtBu)21041

187

Asn(Trt)-3Pal-Sarc-Amide resin. After -15 minutes, an additional aliquot of D1C (2.6 eq, 2.65 ml) is added to the reaction. Once the reaction is complété as determined by the Kaiser test, the resin iss again washed 3x with DMF prior to starting the next deprotection/coupling cycle.

[00450] Step 9: Coupling of FMOC-Lys(Ac)-OH : The FMOC îs removed from the N-terminus of the resin bound peptide and the resin washed as previously described. FMOC-Lys(Ac)-OH (2 eq, 5.4 g) is dissolved in 100 ml of DMF along with Oxyma (3 eq, 2.81 g). DIC (2.6 eq, 2.65 ml) is added for preactivation of the acid -15 minutes prior to addition to the Pen(Trt)-AEF-Nal-THPGlu(OtBu)-Asn(Trt)-3Pal-Sarc-Amide resin. After-15 minutes, an additional aliquot of DIC (1.4 eq, 1.43 ml) is added to the reaction. Once the reaction was complété as determined by the Kaiser test, the resin is again washed 3x with DMF prior to starting the next deprotection/coupling cycle. [00451] Step 10: Coupling of FMOC-7-Me-Trp-OH : The FMOC is removed from the N-terminus of the resin bound peptide and the resin washed as previously described. FMOC-7-Me-Trp-OH (2 eq, 5.81 g) is dissolved in 100 ml of DMF along with Oxyma (3 eq, 2.81 g). DIC (2.6 eq, 2.65 ml) îs added for preactivation of the acîd -15 minutes prior to addition to the Lys(Ac)-Pen(Trt)-AEFNal-THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-Amide resin. After-15 minutes, an additional aliquot of DIC (1.4 eq, 1.43 ml) îs added to the reaction. Once the reaction is complété as determined by the Kaiser test, the resin is again washed 3x with DMF prior to starting the next deprotection/coupling cycle.

[00452] Step 11 : Coupling of FMOC-Thr(tBu)-OH : The FMOC is removed from the N-terminus of the resin bound peptide and the resin washed as previously described. FMOC-Thr(tBu)-OH (4 eq, 10.5g) is dissolved in 100 ml of DMF along with Oxyma (6 eq, 5.62 g). DIC (5.2 eq, 5.3 ml) is added for preactivation of the acid —15 minutes prior to addition to the 7MeTrp-Lys(Ac)Pen(Trt)-AEF-Nal-THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-Amide resin (SEQ ID NO:529). After -15 minutes, an additional aliquot of DIC (2.6 eq, 2.65 ml) is added to the reaction. Once the reaction is complété as determined by the Kaiser test, the resin is again washed 3x with DMF prior to starting the next deprotection/coupling cycle.

[00453] Step 12: Coupling of FMOC-Asn(Trt)-OH : The FMOC is removed from the N-terminus of the resin bound peptide and the resin washed as previously described. FMOC-Asn(Trt)-OH (4 eq, 15.8 g) is dissolved in 100 ml of DMF along with Oxyma (6 eq, 5.62 g). DIC (5.2 eq, 5.3 ml) is added for preactivation of the acid -15 minutes prior to addition to the Thr(tBu)-7MeTrpLys(Ac)-Pen(Trt)-AEF-Nal-THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-Amide resin (SEQ ID NO:530). After -15 minutes, an additional aliquot of DIC (2.6 eq, 2.65 ml) îs added to the reaction. Once

188 the reaction is complété as determined by the Kaiser test, the resin is again washed 3x with DMF prior to starting the next deprotection/coupling cycle.

[00454] Step 13: Coupling of FMOC-Pen(Trt)-OH : The FMOC is removed from the N-terminus of the resin bound peptide and the resin washed as prevîously described, FMOC- Pen(Trt)-OH (2 eq, 8.1 g) is dissolved in 100ml of DMF along with Oxyma (3 eq, 2.81 g). DIC (2.6 eq, 2.65 ml) is added for preactivation of the acid ~15 minutes prior to addition to the Asn(Trt)-Thr(tBu)7MeTrp-Lys(Ac)-Pen(Trt)-AEF-Nal-THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-Amide resin (SEQ ID NO:531). After-15 minutes, an additional aliquot of DIC (2.6 eq, 2.65 ml) is added to the reaction. Once the reaction is complété as determined by the Kaiser test, the resin is again washed 3x with DMF prior to the final deprotection and acetic acid capping ofthe constructed peptide.

[00455] Step 14: Acetyl Capping: The FMOC is removed from the N-terminus of the resin bound peptide and the resin washed as prevîously described. 150 ml of Capping Reagent A (THF/Acetic anhydride/Pyridine, 80:10:10) is added to the constructed Pen(Trt)-Asn(Trt)-Thr(tBu)-7MeTrpLys(Ac)-Pen(Trt)-AEF-Nal-THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-Amide resin (SEQ IDNO: 532) and shaken for 30 min. The resin îs washed 3 x with DMF followed by 5x with DCM. The resin is divided into 5 - 50 ml centrifuge tubes and placed under vacuum for 1.5 hrs prior to cleavage with TFA.

[00456] Step 15: TFA Cleavage and Ether précipitation: 200 ml of the TFA cleavage cocktail (90/5/2.5/2.5 TFA/water/Tips/DODT) is prepared. 40 ml ofthe cleavage cocktail is added to each of the 5 tubes containing the protected resin bound peptide and shaken for two hours. The spent resin is fdtered away and the fïltrate divided evenly into 18 - 50 ml centrifuge tubes for précipitation. Cold diethyl ether is added to each forming a white precipitate that îs then centrîfuged. The ether is decanted to waste and 2 more ether washes of the precipitate are performed. The resulting white precipitate cake is dried ovemight in the hood to give the crude reduced peptide.

[00457]Step 16: Disulfïde Oxidation: The crude peptide is oxidized and purified in four IL batches. ~ 2.5 g of crude peptide is dissolved in IL 20% ACN/water. With stirring, a saturated solution of iodîne in acetic acid/methanol is added dropwise to the IL peptide solution until the yellow/brown color of the L remains and does not fade away. The light yellow solution is allowed to sit for 5 min prior to quenching the excess I₂ with a pinch of ascorbic acid.

[00458] Step 17: RP-HPLC purification: The RP-HPLC purification is performed s immediately foilowing each 12 oxidation. A préparative purification column (Phenomenex, Luna, Cl 8(2), Ι00Α, 250x50mm) is equilibrated at 70ml/min with 20%MPB in MPA (MPA = 0.1% TFA/water,

189

MPB = 0.1% TFA in ACN). The l L of quenched oxidized peptide is loaded onto the equilibrated column at 70 ml/min. After the solvent front elutes, a gradient of 25-45% MPB at 70ml/min is run over 60 min. The desired material is isolated in fractions and each are analyzed by analytical RPHPLC. Pure fractions are combined from ail four purifications and lyophilized to give purified TFA sait ready for counterion exchange.

[00459]Step 18: Counterion Exchange to Acetate: The same préparative RP-HPLC column is equilibrated with 5% MPB in MPA at 70 ml/min (MPA = 0.3% AcOH in Water, MPB = 0.3% AcOH in ACN, MPC = 0.5M NH4OAc in Water.) The purified peptide TFA sait is dissolved in 50/50 ACN/water and diluted to 15% ACN. The solution is loaded onto the equilibrated column at 70 ml/min and the solvent front is eluted. The captured peptide is washed with 5% MPB in MPA for 5 min. The captured peptide is then washed with 5% MPB in MPC for 40 min at 70 ml/min to exchange the cou nierions to Acetate. The captured peptide is washed with 5% MPB in MPA at 70mI/min for J 0 min to clear ail NH4OAc from the system. Finally, the peptide is eluted with a gradient of 5-70% MPB in MPA over 60 minutes and collected in fractions.

[00460] Step 19: Final Lyophilization and Analysis: The collected fractions are analyzed by analytical RP-HPLC, and ail fractions >95% purity are combined. Lyophilization of the combined fractions gives Peptide #104 as a white powder with a purity >95 % as determined by RPHPLC. Peptide identity îs confirmed with LC/MS of the purified Peptide #104, giving 2 charged States of the peptide, M+2/2 of 950 amu and the molecular ion of 1899 amu.

EXAMPLE I C: ADDITIONAL REPRESENTATIVE SYNTHESIS OF PEPTIDE MONOMERS - SYNTHESIS OF PEPTIDE Ac-rPenl*-N-T-rWÎ7-Ph)l-[Lvs(Ac)HPen]*Phei4-(2-aminoethoxv)l-r2-Nall-[THPl-E-N-l3-Pan-Sarc-NH2 UPEN-PEN FORM DISULFIDE BOND) (SEQ. ID. NO. 106) (PEPTIDE #106)

[Û0461]The synthesis of Peptide #106 is prepared using FMOC solid phase peptide synthesis techniques.

[00462]The Peptide #106 is constructed on Rînk Amide MBHA resin using standard FMOC protection synthesis conditions reported în the literature. The constructed peptide is isolated from the resin and protecting groups by cleavage with strong acid followed by précipitation. Oxidatîon to form the disulfide bond is performed followed by purification by RPHPLC and counterion exchange. Lyophilization of pure fractions gives the final product Peptide #433.

[00463] Swell Resin: 10 g of Rink Amide MBHA solid phase resin (0.66mmol/g loadîng) is transferred to a 250 ml peptide vessel with filter frit, ground glass joint and vacuum sîde arm. The resin îs washed 3x with DMF.

190

[00464] Step l: Coupling of FMOC-Sarc-OH: Deprotection of the resin bound FMOC group is realized by adding 2 resin-bed volumes of 20% 4-methyl-piperidine in DMF to the swollen resin and shaking for 3-5 min prier to draining and adding a second, 2-resin-bed volume of the 4-methyl piperidine solution and shaking for an additional 20-30 min. After deprotection the resin is washed 3x DMF with shaking. FMOC-Sarc-OH (3 eq, 6.2 g) is dissolved in 100 ml DMF along with Oxyma (4.5 eq, 4.2.2g). Preactivation of the acid is accomplished by addition of DIC (3.9 eq, 4 ml) with shaking for 15 min prior to addition to the deprotected resin. An additional aliquot of DIC (2.6 eq, 2.65 ml) is then added after ~ 15 min of coupling. The progress of the coupling reaction is monitored by the colorimétrie Kaiser test. Once the reaction is judged complété the resin is washed 3 x DMF with shaking prior to starting the next deprotection/couplîng cycle.

[00465] Step 2: Coupling of FMOC-3Pal-OH: FMOC deprotection is again accomplished by adding two séquentiel, 2-resin-bed volumes of 20% 4-methyl-piperidine in DMF, one times 3-5 minutes and one times 20-30 minutes, draining in between treatments. The resin is then washed 3 times prior to coupling with protected 3-pyridy] alanine (3Pal). FMOC-3Pal-OH (3 eq, 7.8g) is dissolved in DMF along with Oxyma (4.5eq, 4.22g). Preactivation with DIC (3.9 eq, 4 ml) for 15 minutes is donc prior to addition to the Sarc-Amide resin. After 15 minutes, an additional aliquot of DIC (2.6 eq, 2.65 ml) is added to the reaction. Once the reaction is complété as determined by the Kaiser test, the resin is again washed 3x with DMF prior to starting the next deprotection/coupling cycle.

[00466] Step 3: Coupling of FMOC-Asn(Trt)-OH; The FMOC îs removed from the N-terminus of the resin bound 3Pal and washed as previously described. FMOC-Asn(Trt)-OH (2eq, 8g) is dissolved in 100ml of DMF along with Oxyma (3eq, 2.81g). DIC (2.6 eq, 2.65 mi) is added for preactivation of the acid for~l 5 minutes prior to addition to the 3Pal-Sarc-Amide resin. After -15 minutes, an additional aliquot of DIC (1.4 eq, 1.43 ml) is added to the reaction. Once the reaction is complété as determined by the Kaiser test, the resin is washed 3x with DMF prior to starting the next deprotection/coupling cycle.

[00467] Step 4: Coupling of FMOC-Glu(OtBu)-OH; The FMOC is removed from the N-terminus ofthe resin bound Asparigine and the resin washed with DMF as previously described. FMOCGlu(OtBu)-OH (2 eq, 5.91 g) is dissolved in 100ml of DMF along with Oxyma (3eq, 2.81g). DIC (2.6 eq, 2.65 ml) is added for preactivation ofthe acid-15 minutes prior to addition to the Asn(Trt)3Pal-Sarc-Amide resin. After-15 minutes, an additional aliquot of DIC (1.4 eq, 1.43 ml) is added to the réaction. Once the reaction is complété as determined by the Kaiser test the resin is washed 3x with DMF prior to starting the next deprotection/coupling cycle.

I9I

[00468] Step 5: Coupling of FMOC-THP-OH: The FMOC is removed from the N-terminus of the resin bound peptide and the resin is washed as previously described. FMOC-THP-OH (3 eq, 7.36 g) is dissolved in 100ml of DMF along with Oxyma (4.5 eq, 4.22g). DIC (3.9 eq, 4 ml) is added for preactivation of the acid -15 minutes prîor to addition to the Glu(OtBu)-Asn(Trt)-3Pal-SarcAmide resin. After -15 minutes, an additional alîquot of DIC (2.6 eq, 2.65 ml) is added to the reaction. Once the reaction is complété as determined by the Kaiser test the resin is washed 3x with DMF prior to starting the next deprotection/coupling cycle.

[00469] Step 6: Coupling of FMOC-L-Ala(2-NaphthyI)-OH (Nal): The FMOC îs removed from the N-terminus of the resin bound peptide and the resin washed as previously described. FMOCL-Ala(2-Naphthyl)-OH (3 eq, 8.66 g) is dissolved in 100ml of DMF along with Oxyma (4.5 eq, 4.22g). DIC (3.9 eq, 4 ml) is added for preactivation of the acid ~15 minutes prior to addition to the THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-Amide resin. After -15 minutes, an additional aliquot of DIC (2.6 eq, 2.65 ml) is added. Once the reaction is complété as determined by the Kaiser test the resin was again washed 3x with DMF prior to starting the next deprotection/coupling cycle.

[00470] Step 7: Coupling of FMOC-4-[2-(Boc-amino-ethoxy)]-L-Phenylalanine (FMOC-AEF): The FMOC îs removed from the N-terminus of the resin bound peptide and the resin washed as previously described. FMOC-4-[2-(Boc-amino-ethoxy)]-L-Phenylalanine (3 eq, 10.8 g) îs dissolved in 100ml of DMF along with Oxyma (4.5 eq, 4.22g). DIC (3.9 eq, 4 ml) is added for preactivation of the acid ~15 minutes prior to addition to the Nal-THP- Glu(OtBu)-Asn(Trt)-3PalSarc-Amide resin. After -15 minutes, an additional aliquot of DIC (2.6 eq, 2.65 ml) is added to the reaction. Once the réaction is complété as determined by the Kaiser test the resin is washed 3x with DMF prior to starting the next deprotection/coupling cycle.

[00471] Step 8; Coupling of FMOC-Pen(Trt)-OH : The FMOC is removed from the N-terminus of the resin bound peptide and the resin washed as previously described. FMOC-Pen(Trt)-OH (3 eq, 12.14 g) îs dissolved in 100ml of DMF along with Oxyma (4.5 eq, 4.22g). DIC (3.9 eq, 4 ml) îs added for preactivation of the acid -15 minutes prior to addition to the AEF-Nal-THP-Glu(OtBu)Asn(Trt)-3Pal-Sarc-Amide resin. After ~15 minutes, an additional aliquot of DIC (2.6 eq, 2.65 ml) îs added to the réaction. Once the reaction is complété as determined by the Kaiser test, the resin is again washed 3x with DMF prior to starting the next deprotection/coupling cycle.

[00472] Step 9: Coupling of FMOC-Lys(Ac)-OH : The FMOC is removed from the N-terminus of the resin bound peptide and the resin washed as previously described. FMOC-Lys(Ac)-OH (2 eq, 5.4 g) is dissolved in 100 ml of DMF along with Oxyma (3 eq, 2.81 g). DIC (2.6 eq, 2.65 ml) is added for preactivation of the acid -15 minutes prior to addition to the Pen(Trt)-AEF-Nal-THP

192

Glu(OtBu)-Asn(Trt)-3Pal-Sarc-Amide resin. After-I5 minutes, an additional aliquot of DIC (1.4 eq, l .43 ml) is added to the reaction. Once the reaction was complété as determined by the Kaiser test, the resin îs again washed 3x with DMF prior to starting the next deprotection/coupling cycle. [00473] Step 10: Coupling of FMOC-7-Phe-Trp-OH : The FMOC is removed from the N-terminus of the resin bound peptide and the resin washed as previously described. FMOC-7-Ph-Trp-OH (2 eq, 5.81 g) is dissolved in 100 ml of DMF along with Oxyma (3 eq, 2.81 g). DIC (2.6 eq, 2.65 ml) îs added for preactivation ofthe acid ~15 minutes prior to addition to the Lys(Ac)-Pen(Trt)-AEFNal-THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-Amide resin. After ~15 minutes, an additional aliquot of DIC (l .4 eq, l .43 ml) is added to the reaction. Once the reaction is complété as determined by the Kaiser test, the resin is again washed 3x with DMF prior to starting the next deprotection/coupling cycle.

[00474] Step 11: Coupling of FMOC-Thr(tBu)-OH : The FMOC is removed from the N-terminus of the resin bound peptide and the resin washed as previously described. FMOC-Thr(tBu)-OH (4 eq, 10.5g) is dissolved in 100 ml of DMF along with Oxyma (6 eq, 5.62 g). DIC (5.2 eq, 5.3 ml) is added for preactivation of the acid ~I5 minutes prior to addition to the 7PhTrp-Lys(Ac)Pen(Trt)-AEF-Nal-THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-Amide resin. After -15 minutes, an additional aliquot of DIC (2.6 eq, 2.65 ml) is added to the reaction. Once the reaction is complété as determined by the Kaiser test, the resin is again washed 3x with DMF prior to starting the next deprotection/coupling cycle.

[00475] Step 12: Coupling of FMOC-Asn(Trt)-OH : The FMOC is removed from the N-terminus of the resin bound peptide and the resin washed as previously described. FMOC-Asn(Trt)-OH (4 eq, 15.8 g) is dissolved in I00 ml of DMF along with Oxyma (6 eq, 5.62 g). DIC (5.2 eq, 5.3 ml) îs added for preactivation of the acid —15 minutes prior to addition to the Thr(tBu)-7PhTrpLys(Ac)-Pen(Trt)-AEF-Nal-THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-Amide resin (SEQ ID NO; 533). After ~15 minutes, an additional aliquot of DIC (2.6 eq, 2.65 ml) is added to the reaction. Once the reaction is complété as determined by the Kaiser test, the resin is again washed 3x with DMF prior to starting the next deprotection/coupling cycle.

[00476] Step 13: Coupling of FMOC-Pen(Trt)-OH ; The FMOC is removed from the N-terminus ofthe resin bound peptide and the resin washed as previously described. FMOC- Pen(Trt)-OH (2 eq, 8.1 g) is dissolved in 100ml of DMF along with Oxyma (3 eq, 2.81 g). DIC (2.6 eq, 2.65 ml) is added for preactivation of the acid -15 minutes prior to addition to the Asn(Trt)-Thr(tBu)7PhTrp-Lys(Ac)-Pen(Trt)-AEF-Nal-THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-Amide resin (SEQ ID NO: 534). After -15 minutes, an additional aliquot of DIC (2.6 eq, 2.65 ml) is added to the reaction.

I93

Once the reaction is complété as determîned by the Kaiser test, the resm is again washed 3x with DMF prior to the final deprotection and acetîc acid capping of the constructed peptide.

[00477] Step 14: Acetyl Capping: The FMOC is removed from the N-terminus of the resin bound peptide and the resin washed as previously described. 150 ml of Capping Reagent A (THF/Acetic anhydride/Pyridine., 80:10:10) is added to the constructed Pen(Trt)-Asn(Trt)-Thr(tBu)-7PhTrpLys(Ac)-Pen(Trt)-AEF-Nal-THP-Glu(OtBu)-Asn(Trt)-3Pal-Sarc-Amide resin (SEQ ID NO: 535) and shaken for 30 min. The resin is washed 3 x with DMF followed by 5x with DCM. The resin is divided into 5 - 50 ml centrifuge tubes and placed under vacuum for 1.5 hrs prior to cleavage with TFA.

[00478]Step 15: TFA Cleavage and Ether précipitation: 200 ml of the TFA cleavage cocktail (90/5/2.5/2.5 TFA/water/Tips/DODT) is prepared. 40 ml ofthe cleavage cocktail is added to each of the 5 tubes containîng the protected resin bound peptide and shaken for two hours. The spent resin is filtered away and the fîltrate divided evenly into 18 - 50 ml centrifuge tubes for précipitation. Cold diethyl ether is added to each fonning a white precipitate that is then centrifuged. The ether is decanted to waste and 2 more ether washes of the precipitate are performed. The resulting white precipitate cake is dried ovemight in the hood to give the crude reduced peptide.

[00479]Step 16: Disulfide Oxîdation: The crude peptide is oxidized and purified in four IL batches. ~ 2.5 g of crude peptide is dissolved in IL 20% ACN/water. With stirring, a saturated solution of iodine in acetic acid/methanol is added dropwise to the IL peptide solution until the yellow/brown color of the b remains and does not fade away. The light yellow solution is allowed to sit for 5 min prior to quenchîng the excess b with a pînch of ascorbic acid.

[00480] Step 17: RP-HPLC purification: The RP-HPLC purification is performed s immediately following each 12 oxîdation. A préparative purification column (Phenomenex, Luna, C!8(2), 100A, 250x50mm) is equilibrated at 70ml/min with 20% MPB in MPA (MPA = 0.1 % TFA/water, MPB = 0.1 % TFA in ACN). The 1 L of quenched oxidized peptide is loaded onto the equilibrated column at 70 ml/min. After the solvent front elutes, a gradient of 25-45% MPB at 70ml/min is run over 60 min. The desired material is isolated in fractions and each are analyzed by analytical RPHPLC. Pure fractions are combined from ail four purifications and lyophilized to give purified TFA sait ready for counterion exchange.

[00481]Step 18: Counterion Exchange to Acetate: The same préparative RP-HPLC column is equilibrated with 5% MPB in MPA at 70 ml/min (MPA = 0.3% AcOH in Water, MPB = 0.3% AcOH in ACN, MPC = 0.5M NH4OAc in Water.) The purified peptide TFA sait is dissolved in

194

50/50 ACN/water and diluted to 15% ACN. The solution is loaded onto the equihbrated column at 70 ml/min and the solvent front is eluted. The captured peptide is washed with 5% MPB in MPA for 5 min. The captured peptide is then washed with 5% MPB in MPC for 40 min at 70 ml/min to exchange the counterions to Acetate. The captured peptide îs washed with 5% MPB in MPA at 70ml/mîn for 10 min to clear ail NH4OAc from the system. Finally, the peptide is eluted with a gradient of 5-70% MPB in MPA over 60 minutes and collected in fractions.

[00482] Step 19: Final Lyophilization and Analysis: The collected fractions are analyzed by analytical RP-HPLC, and ail fractions >95% purity are combined. Lyophilization of the combined fractions gives Peptide #106 as a white powder with a purity >95 % as determined by RPHPLC. Peptide identity is confirmed with LC/MS of the purified Peptide #106, giving 2 charged States of the peptide, M+2/2 of 981 amu and the molecular ion of 1961 amu.

EXAMPLE 2: PEPTIDE INHIBITION OF BINDING OF INTERLEUK.1N-23 TO THE

INTERLEUKIN-23 RECEPTOR

[00483]Peptide optimîzation was performed to îdentify peptide inhîbîtors of IL-23 signalling that were active at low concentrations (e.g., IC50 <10 nM). Peptides were tested to îdentify peptides that inhibit the binding of IL-23 to human IL-23R and inhibit IL-23/IL-23R functîonal activity, as described below.

[00484] Assays were performed to détermine peptide activity as described below, and the results of these assays are provided in Table El A and Table E1B. Human ELISA indicates the IL23IL23R compétitive binding assay described below, Rat ELISA indicates the rat IL-23R compétitive binding ELISA assay described below, and pStat3HTRF indicates the DB cells 1L23R pSTAT3 cell assay described below. The peptides depicted in Table El A and Table El B are cyclized via a disulfide bridge formed between two Pen residues in these peptides. The peptides depicted in Table E2 are cyclized via a thioether bond between the indîcated amino acid residues. Table E2 provides an illustrative structure depicting thioether cyclization, which is indîcated in the table by the term “cyclo,” with the cyclic région bracketed immedîately following the term “cyclo.” For certain peptides, the residue Abu is présent where indîcated, whereas in other embodiments, e.g., those related to the non-cyclized form, the Abu may be referred to as a hSer(CI) or homoSer residue.

IL23-IL23R Compétitive Binding ELISA

[00485] An Immulon® 4HBX plate was coated with 50 ng/well of IL23R_huFC and incubated overnight at 4°C. The wells were washed four times with PBST, blocked with PBS containing 3% Skim Milk for 1 hour at room température, and washed again four times with PBST. Serial

195 dilutions of test peptides and IL-23 at a final concentration of 2 nM dduted in Assay Buffer (PBS containing l % Skini Milk) were added to each well, and incubated for 2 hours at room température. After the wells were washed, bound IL-23 was detected by incubation with 50 ng/well of goat antip40 polyclonal antibodies (R&D Systems #AF309) diluted in Assay Buffer for l hour at room température. The wells were again washed four times with PBST. The secondary antibodies, HRP conjugated donkey anti-goat IgG (Jackson ImmunoResearch Laboratories #705-035-147) diluted 1:5000 în Assay Buffer was then added, and incubated for 30 minutes at room température. The plate was finally washed as above. Signais were visualized with TMB One Component HRP Membrane Substrate, quenched with 2 M sulfuric acid and read spectrophotometrically at 450 nm. IC50 values for various test peptides determined from these data are shown in Table El A and Table E1B.

Rat 1L-23R Compétitive Binding ELISA

[00486] An assay plate was coated with 300 ng/well of Rat IL-23R_huFC and incubated overnight at 4°C. The wells were washed, blocked, and washed again. Serial dilutions of test peptides and IL-23 at a final concentration of 7 nM were added to each well, and incubated for 2 hours at room température. After the wells were washed, bound IL-23 was detected with goat anti-p40 polyclonal antibodies, followed by an HRP conjugated donkey anti-goat IgG. Signais were visualized with TMB One Component HRP Membrane Substrate and quenched with 2 M sulfuric acid. IC50 values for various test peptides determined from these data are shown in Table El A-E3B.

PB Cells IL23R pSTAT3 Cell Assay

[00487] IL-23 plays a central rôle in supporting and maintaîning Thl 7 différentiation in vivo. This process is thought to be mediated primarily through the Signal Transducer and Activator of Transcription 3 (STAT3), with phosphorylation of STAT3 (to yield pSTAT3) leading to upregulation of RORC and pro-inflammatory IL-17. This cell assay examines the levels of pSTAT3 in IL-23R-expressing DB cells when stimulated with IL-23 in the presence of test compounds. Serial dilutions of test peptides and IL-23 (Humanzyme #HZ-1261) at a final concentration of 0.5 nM, were added to each well in a 96 well tissue culture plate (Corning #CLS3894). DB cells (ATCC #CRL-2289), cultured in RPMI-1640 medium (Thermo Scientific #11875093) supplemented with 10% FBS, were added at 5 X 10E5 cells/well and incubated for 30 minutes at 37°C in a 5% COj humidified incubator. Changes in phospho-STAT3 levels in the cell lysâtes were detected using the Cisbio HTRF pSTAT3 (Tyr705) Cellular Assay Kit (Cisbio #62AT3PEH), according to manufacturer’s Two Plate Assay protocol. IC50 values determined k I96 from these data are shown in Table El A and Table El B. Where not shown or it is marked as “0”, data was not y et determined,

PB MC pSTAT3 assav

[00488] Cryopreserved peripheral blood mononuclear cells (PBMCs) from healthy donors were 5 thawed and washed twice in ImmunoCult-XF T cell expansion medium (XF-TCEM) supplemented with CTL anti-aggregate wash. The cells were counted, resuspended at 2xl0⁵ cells per mL XF-TCEM supplemented with penicillin/streptomycin and 100 ng/mL IL-1 β (BioLegend, 579404), and cultured in tissue culture flasks coated with anti-CD3 (eBioscience, 16-0037-85 or BD Pharmingen, 555329) at 37°C in 5% CO₂. On day 4 of culture, PBMCs were collected, washed 10 twice in RPMI-1640 supplemented with 0,1% BSA (RPMI-BSA), and incubated in RPM1-BSA in uprîght tissue culture flasks for 4 hours at 37°C in 5% CO₂. Followîng this ‘starvation,’ a total of 6x10⁴ cells in 30 pL RPMI-BSA was transferred into each well of a 384-well plate pre-spotted with peptide or DMSO. The cells were incubated for 30 minutes prior to the addition of IL-23 at a final concentration of 5 ng/mL. The cells were stimulated with cytokine for 30 minutes at 37°C 15 în 5% CO₂, transferred onto ice for 10 minutes, and lysed. Cell lysâtes were stored at -80°C until phosphorylated STAT3 was measured using the phospho-STAT panel kit (Meso Scale Discovery, K15202D).

Table El A. ICsqs of Additional Illustrative Peptides ofthe present invention

SEQ ID No. / Peptide No.	Sequence*	pStat3 HTRF (nM)	PBMC pSTAT3 (nM)
1	Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Ph)]-[Lys(Ac)]-[Cys]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]- N-dK-[Sarc]-NH2	12.3
2	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[3-Quin]-[a-MeLys]-[Lys(Ac)]-N|(D)Leu)]-[Sarc]-NI-I2	0.742
3	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)l-[3-Quin]-[THP]-E-N-[(D)Lys]-[Sarc]nh2	0.456
4	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[3-Quin]-[a-MeLys]-[Lys(Ac)]-N[(D)His]-[Sarc]-NH2	0.722
5	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[3-Quin]-[a-MeLys]-[Lys(Ac)]-N-H[Sarc]-NH2	0.209	2.6
6	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[3-Quin]-[THP]-E-N-[(D)Leu)]-[Sarc]- NH2__	0.405	4.4

197

SEQ ID No. / Peptide No.	Sequence*	pStat3 HTRF (nM)	PBMC pSTAT3 (nM)
7	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[3-Quin]-[a-MeLys]-[Lys(Ac)]-N- [(D)Lys]-[Sarc]-NH2	0.877
8	Ac- [(D)Arg]- [ Abu]-Q-T-W-Q-[Cys] -Phe[4-(2am i noethoxy)] - [2-Nal]-[THP]-E-N-N- [(D)NMeTyr] NH2;		1
9	Ac- [(D)Arg] - [Pen]-Q-T- W-Q- [Pen]- Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-N-[(D)NMeTyr]NH2;		24
10	Ac-[(D)Arg]-[Pen]-Q-T-W-Q-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-[aMeGlu]-N-F[(D)NMeTyr]-NH2;		4.3
11	Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[3Quin]-[THP]-E-N-[(D)Lys]-[Sarc]NHj;	0.433	5.4
12	Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[3Quin]-[a-MeLys]-[Lys(Ac)]-N[(D)Lys]-[Sarc]-NH2;	0.519	10
13	Ac-[Pen]-N-T-[W(7-Ph)l-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[3Quin]-[THP]-E-N-[(D)Leu]-[Sarc]- NH2;	0.319
14	Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[3Quin]-[a-MeLys]-[Lys(Ac)]-N[(D)Leu]-[Sarc]-NH2;	0.573
15	Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2ami noethoxy )]-[3 Qui n]-[THP]-E-N-H-[Sarc]-NH2;	0.264	2.2
16	Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[3Quin]-[a-MeLys]-[Lys(Ac)]-N-H[Sarc]-NH2;	0.156	1.9
17	Ac-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2ami noethoxy)]-[2-Nal] -[a-MeLys]-[Lys(A c)]-N[(D)Lys]-[Sarc]-NH2;	0.791
18	Ac-[Abu]-Q-T-[W(7-Ph)]-[Lys(Ac)HCys]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N[(D)Lys]-[Sarc]-NH2;	1.1
19	Ac-[Pen] -N-T- [ W(7-Me)] -[Ly s(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-NaI]-[a-MeLys]-[Lys(Ac)]-N[(D)Leu]-[NMeLeu]-NH2;	3.24
20	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N|(D)Leu]-[ Sarc]-NH2 ;	0.391
21	Ac-[Pen]-N-T- [ W(7-Me)] - [Ly s( Ac)]-[Pen] - Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)j-N[(D)Lys]-[Sarc]-NH2;	0.542
22	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-H-[Sarc]-NH2;	0.166	0.51

198

SEQ ID No. / Peptide No.	Sequence*	pStat3 HTRF (nM)	PBMC pSTAT3 (nM)
23	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-H[Sarc]-NH2;	0.234	0.78
24	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-[(D)Leu]-[Sarc]-NH2;	0.446
25	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2am inoethoxy )]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N[(D)Leu]-[Sarc]-NH?;	0.487
26	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Giy)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-H-[Sarc]-NH2;	0.224	0.95
27	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2am inoethoxy )]-[2-Nal]-(a-MeLy s]-[Lys(Ac)]-N-H[Sarc]-NH2;	0.334
28	Ac-(Pen]-N-T-[W(7-Me)]-[Lys(Gly)J-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Na(]-[THP]-E-N-[(D)Leu]-[Sarc]-NH2;	0.358
29	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2- aminoethoxy)H2-Nal]-[a-MeLys]-[Lys(Ac)]-N[(D)Leu]-[Sarc]-NH2;	0.974
30	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(bAla)]-[Pen]-Phe[4-(2am inoethoxy)] - [2-Nal]-[THP ]-E-N-H-[Sarc] -NH 2 ;	0.207
31	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(bAla)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nai]-[a-MeLys]-[Lys(Ac)]-N-H[Sarc]-NH2;	0.42
32	Ac-[Pen]-N-T-[W(7-Et)]-[Lys(Ac)]-(Pen]-Phe[4-(2am inoethoxy )] - [2-Nal]-[THP] -E-N-H- [ Sarc] -NH2;	0.I71	1.4
33	Ac-[Pen] -N-T- (W(7-Et)] - [Ly s(Ac)]-[Pen]-Phe [4-(2aminoethoxy)]-[2-Nal] - [a-MeLy s] -[Ly s( Ac)] -N-H[Sarc]-NH2;	0.251	2.2
34	Ac-[Pen]-N-T-[W(7-Me)HLys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[W(7-Et)]-[a-MeLys]-[Lys(Ac)]-N-H[Sarc]-NH2;	6.92
35	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[W(4-Me)]-[a-MeLys]-[Lys(Ac)]-N-H[Sarc]-NH2;	51.3
36	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[W(6-Me)]-[a-MeLys]-[Lys(Ac)]-N-H[Sarc]-NH2;	Ll
37	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- ,am inoethoxy)] -[W(4-OMe)]-[ a-MeLy s]-[Lys(Ac)]-N-H[Sarc]-NH2;	196
38	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2am inoethoxy)]-[W(7-i-Pr)]-[a-MeLys]-[Lys( Ac)]-N-H[Sarc]-NH2; ________________________	21.7

199

SEQ ID No. / Peptide No.	Sequence*	pStat3 HTRF (nM)	PBMC pSTAT3 (nM)
39	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[W(7-nPr)]-[a-MeLys]-[Lys(Ac)]-N-H[Sarc]-NH2;
40	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[W(7-OMe)]-[a-MeLys]-[Lys(Ac)]-N-H[Sarc]-NH2;	3.8
41	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[W(6-Cl)]-[a-MeLys]-[Lys(Ac)]-N-H[Sarc]-NH2;	0.304
42	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)HW(5-OMe)l-[a-MeLys]-[Lys(Ac)]-N-H[Sarc]-NH2;	5.82
43	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[W(3-MePh)]-[a-MeLys]-[Lys(Ac)]-N-H[Sarc]-NH2;	5.39
44	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[W(6-Ph)]-[a-MeLys]-[Lys(Ac)]-N-H[Sarc]-NH2;	9.26
45	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[W(6-Et)]-[a-MeLys]-[Lys(Ac)]-N-H[Sarc]-NH2;	2.43
46	Ac-[Pen]-N-T-[W(7-(2-FPh)]- [Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-H- ÎSarcl-NH2;	0.373
47	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)J-N[(D)Leu]-[(D)NMeTyr]-NH2;	0.497	1.9
48	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLysl-[Lys(Ac)]-N[(D)Lys]-[(D)NMeTyr]-NH2;	0.679	1.7
49	Ac-[Pen]-N~T-[W(7-(2-OMePh)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]N-H-[Sarc]-NH2;	0.853
50	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)HPen]-Phe[4-(2- ammoethoxy)]-[W(7-Pli)Ma-MeLys]-[Lys(Ac)]-N-H[Sarc]-NH2;	2.97
51	Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-H[Sarc]-NH2;	0.114	0.87
52	Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-H-[Sarc]-NH2;	0.076	0.34
53	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)HPen]-Phe[4-(2aminoethoxy)]-[3Quin]-[THP]-E-N-H-[Sarc]-NH2;	0.175	1.8
54	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]42-Nal]-[THP]-E-S-H-[Sarc]-NH2;	0.358

200

SEQ ID No. ! Peptide No.	Sequence*	pStat3 HT RF (nM)	PBMC pSTAT3 (nM)
55	Ac-[Pen]-S-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-H-[Sarc]-NH2;	0.203
56	Ac-[Pen]-S-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-S-H-[Sarc]-NH2;	0.674
57	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-H-[(D)NMeTyr]NH2;	0.26
58	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-F[(D)NMeTyr]-NH2;		19
59	Ac- [Pen] -N-T- [W(7-Ph)Htys(Ac)]-[Pen]-Phe[4-(2am i noethoxy)]-[2-Nal]-[THP]-E-S-H-[Sarc]-NH2;	0.359
60	Ac-[Pen]-S-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2am i noethoxy)] -[2-Nal] - [THP]-E-N-H- [ Sarc]-NH2;	0.264
61	Ac-[Pen]-S-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoeihoxy)]-[2-Nal]-[THP]-E-S-H-[Sarc]-NH2;	0.391
62	Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-H-[(D)NMeTyr]NH2;	0.151
63	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-[(D)Asn]-H-[Sarc]- NH2;	3.23
64	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-G-H-[Sarc]-NH2;	0.604
65	Ac- [Pen]-N-T- [W(7-Me)] - [Ly s(Ac)]-[Pen]-Phe [4-(2ami noethoxy)]-[2-Nal]-[THP]-E-[h(Ser)]-H-[Sarc]-NH2;	0.288
66	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-H-P-NH2;	0.205
67	Ac-[Pen]-N-T-[W(7-(2-Nal))]-[Lys(Ac)]-[Pen]-Phe[4-(2am inoethoxy)]-[2-Nal] -[THP]-E-N-H- [ Sarc] -NH2;	0.199
68	Ac-[Penl-N-T-[W(7-3BiPh)HLys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-H-[Sarc]-NH2;	0.798
69	A c-[Pen]-N-T-[ W(7-(Phenanthren-5-y !))]-[ Lys(Ac)][Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH2;	3.19
70	Ac-[Pen]-N-T-[W(7-(4-Anthracen-5-yl))]-[Lys(Ac)J[Pen]-Phe[4-(2-aminoethoxy)H2-Nal]-[THP]-E-N-H[Sarc]-NH2;	78.3
71	Ac-[Pen]-N-T-[W(7-(l-Nal))]-[Lys(Ac)]-[Pen]-Phe[4-(2ami noethoxy)]-[2-Nal] -[THP]-E-N-H-[Sarc]-NH2;	0.533
72	Ac-[Pen]-N-T-[W(7-(4BiPh))]-[Lys(Ac)HPen]-Phe[4(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H-[Sarc]-NH2;	0.594

201

SEQ ID No. 1 Peptide No.	Sequence*	pStaG HTRF (nM)	PBMC pSTAT3 (nM)
73	Ac-[Pen]-N-T-[W(7-(3,5-t-Bu-Ph))]-[Lys(Ac)]-[Pen]Phe[4-(2-am inoethoxy )]-[2-Nal]-[TH P]-E-N-H-[Sarc] NH2;	6.24
74	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4- CONH2)]-[2-Nal]-[THP]-E-N-H-[Sarc]-NH2;	1.42
75	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4- OMe)]-[2-Nal]-[THP]-E-N-H-[Sarc]-NH?;	0.291
78	Ac-[Pen] -N-T-[ W(7-Me)]-[Ly s(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[3Quin]-[a-MeLys]-[Lys(Ac)]-N-[2Pa1]NH2;	73.6
79	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[2Pal]NH2;	1.91
80	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]NH2;	0.0688
81	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Na1]-[THP]-[Lys(Ac)]-N-H-[Sarc]- NH2;	0.123
82	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-H[(D)NMeTyr]-NH2;		0.98
83	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]Phe[4-(2-aminoethoxy)]-[2-Na!]-[a-MeLys]-E-N-H[(D)NMeTyr]-NH2;		1.7
84	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-Phe[4aminomethyi]-[(D)NMeTyr]-NH2;		13
85	Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-(Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[aMeLeui-[Lys(Ac)]-N-[(D)His]NH2;		3
86	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2am Î noethoxy )] -[2-Nal]- [a-MeLy s] - [Lys( Ac)] -N[(D)His]-NH2;		7.2
87	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[(D)His][(D)NMeTyr]-NH2;		2000
88	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-N[(D)NMeTyr]-NH2;		>2000
89	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2am i noethoxy)] -[2-Nal]-[a-MeLys]-[Lys( Ac)]-N-N[(D)NMeTyr]-NH2;		6.9
90	Ac-[Pen]-N-T-[ W(7-Me)]-[Ly s(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N- [(D)Val]-[(D)NMeTyr]-NH2;________________________		7.1

202

SEQ ID No. / Peptide No.	Sequence*	pStat3 HTRF (nM)	PBMC pSTAT3 (nM)
91	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Na!]-[a-MeLys]-[Lys(Ac)]-N[(D)Thr]-[(D)NMeTyr]-NH2;		14
92	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[(D)His]NH2;		2.8
93	Ac-[Abu]-N-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2- aminoethoxy)]-[3Quinl-[THP]-E-N-H-[Sarc]-NH2;	0.418
94	Ac-[Abu]-N-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2aminoethoxy)]-[3Quin]-[THP]-E-N-H-[Sarc]-NH2;	0.917
95	Ac-[Abu]-N-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2aminoethoxy)] -[2-Nal]- [a-MeLy s] - [Ly s( Ac)] -N-H[Sarc]-NH2;	0.0818
96	Ac-[ Abu] -N-T- [ W(7-Ph)] -Q- [Cys] -Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-H-[Sarc]-NH2;	0.143
97	Ac-[Abu]-N-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-H[Sarc]-NH2;
98	Ac-[Abu]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Cys]-Phe[4<2am i noethoxy)] - [2-Nal]- [THP]-E-N-H- [Sarc] -NH2;	0.134
99	Ac-[Abu]-N-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-H-[Sarc]-NH2;	0.684
100	Ac-[(D)Arg]-[Abu]-S-T-[W(7-Me)]-Q-[Cys]-Phe[4<2aminoethoxy)]-[2-Nal]-[THP]-E-N-H-[Sarc]-NH2;	1.51
101	Ac-[(D)Arg]-[Abu]-N-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-[(D)Leu]-[Sarc]-NH2;	0.238
102	Ac-[(D)Arg]-[Abu]-N-T-[W(7-Me)]-[Cit]-[Cys]-Phe[4(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H-[Sarc]-NH2;	0.155
103	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal][Sarc]-NH2;	0.0442	0.00775
104	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2;	0.022	0.00515
105	Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal][Sarc]-NH2;	0.146	0.019
106	Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoetboxy)]-[2-Nal]-[THP] -E-N-[3 Pal]- [Sarc] -NH2;	0.044	0.0087
107	Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2;	0.029
108	Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2;	0.022

203

SEQ ID No. / Peptide No.	Sequence*	pStat3 HTRF (nM)	PBMC pSTAT3 (nM)
109	Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[THP]-E-N-[3PalHSarc]-NH2;	0.041
110	Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal][Sarc]-NH2;	0.018
ni	Ac-[Abu]-Q-T-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2am inoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2;	0.014
112	Ac-[Abu]-Q-T-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2- am inoethoxy )]-[2-Nal]-[a-MeLy s]-[Lys(Ac)]-N-[3Pal ][Sarc]-NH2;	0.025
113	Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2- am inoethoxy)]- [2-Nal]-[THP] -E-N- [3 Pal]- [bA] -NH2;	0.057
114	Ac-|Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2- am i noethoxy )] -[2-Nal]-[THP] -E-S-[3 Pal]- [bA]-N H2;	0.035
115	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-[4Pal]-[Sarc]-NH2	0.023
116	A c- [Pen]-N-T-[ W(7-Ph)]-[Ly s(Ac)] - [Pen] -Phe [4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[bA]-NH2	0.029
117	Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2am inoethoxy)] - [2-Nal]-[THP]-[Ly s( Ac)] -N-[3 Pal] [Sarc]-NH2	0.02
118	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Quin]-[Sarc]-NH2	0.057
119	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2amînoethoxy)]-[2-Nal]-[THP]-E-N-[ 7-Aza-tryptophan][Sarc]-NH2	0.672
120	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal][(D)NMeTyr]-NH2	0.066
121	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-NalHTHP]-E-N-[3Pal]-[(D)NMeTyr]nh2	0.043
122	Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pai][(D)NMeTyr]-NH2	0.144
123	Ac-[Pen] -N-T- [ W(7-Ph)] - [Lys( Ac)]-[Pen] -Phe[4-(2- aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[(D)NMeTyr]nh2	0.019
124	Ac-[Pen]-S-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2am inoethoxy)]-[2-Nal ]-[THP]-E-S-[3 Pal ]-[Sarc]-NH2	0.023
125	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[THP]-E-S-[3Pal]-[Sarc]-NH2	0.04
126	Ac-[Pen] -N-T- [W(7-Ph)]-[Cit]-[Pen]-Phe[4-(2- aminoethoxy)l-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2	0.054	|

204

SEQ ID No. ! Peptide No.	Sequence*	pStat3 HTRF (nM)	PBMC pSTAT3 (nM)
127	A.c-[Pen]-N-T-[W(7-Ph)]-Q-[Pen]-Phe[4-(2- am inoethoxy )] -[2-Nal]-[THP] -E-N- [3 Pal] - [Sarc]-NH2	0.0324
130	Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2am inoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3 Pal ][bA]-NH2	0.066
131	Ac-[Pen] -N-T- [ W(7-Ph)] - [Ly s(Ac)]-[Pen] -Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[bA]-NH2
132	Ac-[Pen]-S-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2	0.054
133	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2am inoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3 Pal] [Sarc]-NH2	0.06
134	Ac-[Abu]-Q-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2	0.038
135	Ac-[Abu]-Q-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2- am inoethoxy)]-[2-Nai] - [a-MeLys]-[Ly s(Ac)]-N-[3 Pal][Sarc]-NH2	0.169
136	Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal][Sarc]-NH2		0.011
137	Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2acey lam i noethoxy)]- [2-Nal ] -[THP]- [ Ly s(Ac)] -N-[3 Pal] [Sarc]-NH2	0.06	0.012
138	Ac-[Pen]-E-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2am inoethoxy )]-[2-Nal] -[THP] - [Ly s(Ac)]-N-[3 Pal] [Sarc]-NH2	0.054
139 Ί	Ac-[Pen] -E-T-[ W(7-Ph)j - [ Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pai][Sarc]-NH2	0.077
140	Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2	0.791
141	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2am inoethoxy )]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3 Pal] [Sarc]-NH2	0.889
142	Ac-[Pen]-N-T-[W(7-(3-carboxamidophenyl))]- |Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]- E-N-[3Pal]-[Sarc]-NH2	0.09
143	Ac-[Pen]-N-T-[W(7-pyrimidin-5-yl)]-[Lys(Ac)]-[PenlPhe[4-(2-am i noethoxy)] - [2-Nal] - [THP]-E-N-[3 Pal ] [Sarc]-NH2	0.94
144	Ac-[Pen]-N-T-[W(7-imidazopyridînyl)]-[Lys(Ac)]]Pen]-Phe[4-(2-am inoethoxy )]-[2-Nal]-[THP]-E-NÎ3Pal]-[Sarc]-NH2___	0.316

205

SEQ ID No. ! Peptide No.	Sequence*	pStat3 HTRF (nM)	PBMC pSTAT3 (nM)
145	Ac-[Pen] -N-T- [W(7-Me)]-[Ly s( Ac)]-[Pen]-Phe [4-(2aminoethoxy)]-[2-Na!]-[NMe(Lys)]-[Lys(Ac)]-N[His_3Me]-NH2;	0.029	0.12
146	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[His_3Me]NH2;		0.036
147	A c- [Pen]-N-T-[W(7-(4Quin))]-[Lys(Ac)]-[Pen]-Phe[4- (2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2	0.Û429
148	Ac-[Pen]-N-T-[(W(7-(3-pyrazol-l-yl))]-[Lys(Ac)]-[Pen]Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pai][Sarc]-NH2	0.0682
149	Ac-|Pen]-N-T-[(W(7-(5-Et)HLys(Ac)]-[Pen]-Phe[4-(2ami noethoxy)]-[2-Nal]-[THP]-E-N-[3 Pal ]-[Sarc]-NH2	0.0239
150	Ac-[Pen]-N-T-[W(5-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal ]-[THP]-E-N-[3Pal]-[Sarc]-NH2	>10
151	Ac-[Pen]-N-T-[(W(7-(3-pyrazo)-l-yl))]-[Lys(Ac)]-[PenP Phe[4-(2-am i noethoxy )] -[2-Nal]-[TH P] -E-N- [3 Pal][Sarc]-NH2	0.0615
152	Ac-[Pen]-N-T-[W(7-indazol-5-yt)]-[Lys(Ac)]-[Pen]Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH2	0.0766
153	Ac-[Pen]-N-T-[W(4-F)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2	0.0402
154	Ac-[Pen]-N-T-[W(5-CN)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2	>10
155	Ac-[Pen]-N-T-[W(7-CN)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2	0.0405
156	Ac-[Pen]-N-T-[W(4-OMe)]-[Lys(Ac)J-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[TI-IP]-E-N-[3Pal]-[Sarc]-NH2	0.0852
157	Ac-[Pen]-N-T-[W(4-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2	0.0432
158	Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH3	0.0491	0.011
159	Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy )]-[2-Nal ] - [Acvc] -E-N-[3 Pal] -[Sarc]-NH2	0.17	0.017
160	Ac-[Pen]-N-T-[W(5-Ca)]-[Lys(Ac)]-[Pen]-Phe[4-(2am i noethoxy)]-[2-Nal ]-[THP] -E-N- [3 Pal] -[Sarc] -NH2	>10
161	Ac-[ Pen]-N-T- [T rp_4 Aza] -[Lys(Ac)]-[Pen]-Phe[4-(2am inoethoxy)] - [2-Nal] -[THP]-E-N- [3 Pal ]- [ Sarc]-NH2	0.222
162	Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2	0.0436

206

SEQ ID No. / Peptide No.	Sequence*	pStat3 HTRF (nM)	PBMC pSTAT3 (nM)
163	A c- [Pen] -N-T-W- [Lys(Ac)] -[Pen] - Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pai][Sarc]-NH2	0.017
164	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]Phe[4-(2-am inoethoxy)]-[2-Nal]-[THP]-E-N-[(5Py al)]NH?		0.011
165	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-Me-Lys]-[Lys(Ac)]-N[(5Pyal)]-NH2		0.0053
166	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe(4-(2-aminoethoxy)]-[2-NalHTHP]-E-N-[(!- Me)His]-NH2		8.9
167	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-[(lMe)His]-NH2		14
168	Ac-[Pen]-N -T-[W(7-Me]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-Me-Lys]-[Lys(Ac)]-N-[3Pal]- [(D)NMeTyr]-NH2		0.019
169	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2am inoethoxy)]-[2-Nal]-[a-MeLy s]-[Lys(Ac)]-N-[Ai b]|(D)Thr]-NH2;	0.534
170	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-H-[(D)Pro]-NH2;	0.388

* wherein Cys and Cys, or Pen and Pen form a disulfide bond; and Abu and Cys or Abu and Pen fonn a thîoether bond.

Table E1B. IC50S of Additional illustrative Peptides ofthe présent invention

SEQ ID No. / Peptide No.	Sequence*	pStat3 HTRF (nM)	PBMC pSTAT3 (nM)
201	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[aMeLeu]-E-N-[(D)Lys]- [(D)NMeTyr]-NH2
202	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2am inoethoxy )]-[2-Nal]-[aMeLeu]-E-N-[(D)His][(D)NMeTyr]-NH2
203	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2am inoethoxy)] -[2-Nal]- [a-MeLys]-[Ly s( Ac)]-N- [(D)Orn] [(D)NMeTyr]-NH2		2.9
204	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2atn inoethoxy)]-[2-Nal ]-[a-MeLys]-[Lys( Ac)]-N-[(D)Ser][(D)NMeTyr]-NH2		6.4
205	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2am inoethoxy )] -[2-Nal]- [a-MeLys]- [Lys(Ac)]-N- [(D)Phe] [(D)NMeTyr]-NH2 ___

207

SEQ ID No. / Peptide No.	Sequence*	pStat3 HTRF (nM)	PBMC pSTAT3 (nM)
206	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H-[(D)Tyr]-NH2		0.78
207	Ac-[Pen] -N-T-[ W(7-Me)]-[(D)Tyr] -[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys][(D)NMeTyr]-NH2		3.3
208	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H-P-NH2
209	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4(2-aminoethoxy)]-[2-Nal]-[THPJ-E-N-H-[(D)Pro]-NH2		0.97
210	Ac-[Pen]-N-T-[W(7-Me)]-[Phe(4-CONH2)]-[Pen]-Phe[4(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N- [(D)Lys]-[(D)NMeTyr]-NH2		6.8
211	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- am i noethoxy )] -[2-Nal]- [Acvc]-E-N-(D)Phe [4-NH2] - [Sarc]NH2		3.2
212	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4(2-ami noethoxy)]-[2-Nal]-[THP]-É-N-H-NH2		1.2
213	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)] -[2-Nal]-[a-MeLys]-[ Ly s(Ac)] -N-H-N(H)Me
214	Ac - [ Pen]-N-T-[ W(7 -Me)]- [Phe(4-N H( Ac))]-[Pen]-Phe [4(2-aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N[(D)Ly s] -[(D)NMeTy r] -NH2		5.7
215	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Tyr][(D)NMeTyr]-NH2		7.3
216	Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[aMeLeu]-[Lys(Ac)]-N-[(D)Lys][(D)NMeTyr]-NH2		1.8
217	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2atiiinoethoxy)]-[2-Nai]-[a-MeLys]-[Lys(Ac)]-N-[(D)His][(D)NMeTyr]-NH2		4.2
218	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bAla][(D)NMeTyr]-NH2		15
219	Ac-[Pen|-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bAla][([J)NMeTyr]-NH2		14
220	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bAla][(D)NMeTyr]-NH2		8.4
221	Ac-[(D)Arg] - [Pen]-N -T-[ W(7-Me)] - [Lys( Ac)] - [Pen] -Phe[4(2- am î noethoxy )]-[2-Nal J-[a-MeLy s] -E-N-H-N(H)Me		0.49
222	Ac-[(D)ArgHPen]-N-T-[W(7-Me)HLys(Ac)]-[Pen]-Phe[4- (2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[THP]-P-NH2		8.1
223	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[41 (2-ami noethoxy )]-[2-Nal]-[THP]-E-N-[THP]-[(D)Pro]-NH2		13

208

SEQ ID No. / Peptide No.	Sequence*	pStat3 HTRF (nM)	PBMC pSTAT3 (nM)
224	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4- (2-aminoethoxy )] -[2-Nal] - [ Acvc] -E-N-[bA la] -[Sarc]-NH2		8.7
225	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4(2-ami noethoxy)]-[2-Nai] -[Acvc] -E-N- [(D) Val]-[Sarc]-NH2		12
226	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4(2-aminoethoxy)]-[2-Nal]-[Acvc]-E-N-[(D)Arg]-[Sarc]-NH2		1.7
227	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4- (2-aminoethoxy)]-[2-Nal]-[Acvc]-E-N-[Hph]-[Sarc]-NH2		8.2
228	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy )]-[2-Nal] - [ Acvc]-E-N-Phe[4-NH2]-[Sarc]-NH2		17
229	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4(2-aminoethoxy)] -[2-Nal ] - [ Ac vc] -E-N-Phe[4-NH2]-[Sarc] NH2		5.1
230	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4- (2-aininoethoxy)]-[2-Nal]-[Acvc]-E-N-F-[Sarc]-NH2		9.8
231	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4- (2-am inoethoxy)]-[2-Nal]-[Acvc]-E-N-[THP]-[Sarc]-NH2		9.9
232	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4- (2-aminoethoxy)]-[2-Nal]-[Acvc]-E-N-[(D)Leu]-[Sarc]-NH2		7.7
233	Ac-[(D)Arg]-[Cys]-N-T-[W(7-Me)]-[Lys(Ac)]-[aMeCys]Phe[4-(2-am inoethoxy)]-[2-Nal ]-[Acvc]-E-N-H-[Sarc]-NH2		4.3
234	Ac-[(D)Arg]-[Cys]-N-T-[W(7-Me)]-[Lys(Ac)]-[aMeCys]Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-E-N-[(D)Leu][Sarc]-NH2		16
235	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4(2-aminoethoxy)] -[2-Nal] -[Acvc] -E-N- [ 3 Pal]-[Sarc] -NH2		0.01
236	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[bAfa][Sarc]-NH2		17
237	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoeihoxy)]-[2-Na!]-[a-MeLys]-[Lys(Ac)]-N-[(D)Val][Sarc]-NH2		49
238	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2am î noethoxy )] -[2-Nal]- [a-MeLy s] - [ Lys( Ac)] -N-[(D)A rg] [Sarc]-NH2		8.9
239	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Hph][Sarc]-NH2		76
240	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Tyr][Sarc]-NH2		40
241	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- am inoethoxy )] -[2-Nal ]- [a-MeLys]-[Ly s( Ac )]-N- [(D)T yr][Sarc]-NH2		13
242	Ac-[(D)ArgHPen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[4Pal]-NH2__

209

SEQ ID No. / Peptide No.	Sequence*	pStat3 HTRF (nM)	PBMC pSTAT3 (nM)
243	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[Phe(4CF3)]-[Sarc]-NH2
244	Ao[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy )] - [2-Nal]-[a-MeLys] -[Lys(Ac)] -N-Ty r_CHF2[Sarc]-NH2
245	Ac-[Pen] -N-T- [W( 7-Me)] - [Ly s( Ac)]-[Pen]-Phe[4-(2aminoethoxy )] -[2-Nal] - [a-MeLy s]-[Lys(Ac )]-N- [THP] -Pnh2
246	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal][(D)NMeTyr]-NH2		0.33
247	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4(2- aminoethoxy)]-[2-Nal] -[THP] -E-N- [3 Pal ]- [ Sarc] -NH2		0.0043
248	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[4Pal]-[Sarc]-NH2
249	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[Phe(2- aminomethyl)]-[Sarc]-NH2
250	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4(2-ami noethoxy)]-[2-Nal]-[TH P]-E-N-[3 Pal]-[Pro(4,4di F )]NH2		0.024
251	Ac- [(D)Arg]-[Pen]-N-T- [ W(7-Me)]-[Lys(Ac)]-[ Pen] -Phe[4(2- aminoethoxy)]-[2-Nal]-[THP] -E-N- [3 Pal]- [aMePro]-NH2		0.0055
252	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe(4(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Aib]-NH2		0.046
253	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[a-MeLy s]-[Lys( Ac)]-N-[His(3Me)]-[Sarc]-NH2
261	Ac- [(D)Arg]-[Pen]-N-T- [ W(7-Me)]-[ Ly s( Ac)]- [Pen] -Phe[4(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[His(3-Me)]-[Sarc]NH2	0.046	0.084
262	Ac-[(D)Arg]-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[THP]-E-N-[His(3-Me)]-[Sarc]-NH2		0.29
266	Ac-[(D)Arg]-[Pen]-N-T-ÎW(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4(2- aminoethoxy)]-[2-Nal] -[THP] -E-N- [3Pal]- [Sarc] -NH2		0.81
267	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4- (2-aminoethoxy)]-[2-Nal ]-[THP]-E-N-[3Pal]-N(H)Me		0.027
270	[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-[3 Pal]-[Sarc] -NH2
271	Ac-[(D)ArgHPen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal ]-[THP]-E-N-[3 Pal ]-[Sarc]-NH2
272	Pr-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]- Phe[4(2-(N-propionylamino)ethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH2 _____________________

210

SEQ ÏD No. ! Peptide No.	Sequence*	pStat3 HTRF (nM)	PBMC pSTAT3 (nM)
273	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4- (2-(N-(4-hydroxy-3-methylphenyl) propionylamino) ethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2
274	[N3_Acid]-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)][Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[TH P]-E-N-[3 Pal ][Sarc]-NH2
275	[FPrpTriazoleMe_Acid]-[(D)Arg]-[Pen]-N-T-[W(7-Me)][Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2
276	Ac-[(D) Arg] - [Pen] -N-T-[ W(7-Me)]-[Lys(Ac)] - [Pen] -Phe[4(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal(5-Me)]-(Sarc]nh2
277	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pa1(5-NH2)][Sarc]-NH2
278	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[THP]-E-N-[His(3-Me)]-N(H)Me
279	Ac- [(D)A rg]-[Pen]-N-T- [ W(7-Me)]-[Lys(Ac)]-( Pen ] -Phe [4(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[(D)NMeTyr]NH2
280	Ac-[(D)Arg] - [Pen] -N-T-[ W(7-M e) ] - [Lys( Ac)] - [Pen] -Phe[4(2-ami noethoxy)] - [2-Nal]-[THP]-E-N-[3Pal]-[Gly(Ncydohexylmethyl)]-NH2
281	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Gly(Nisobutyl)]-NH2
282	Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4~ (2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal(3-Me)]-NH2
283	Ac-[(D)Arg]-[aMeCys]-N-T-[W(7-Me)]-[Lys(Ac)]-[Cys]Ph e[4-(2-ami noethoxy)]-[2-Nal ]-[THP]-E-N-[3 Pal]-[Sarc]nh2
284	Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)][2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2
285	Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]- [2-Nal]-[Acvc]-E-N-[3Pal]-[Sarc]-NH2
286	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4- CONH2)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2	0.0274
287	Ac-[Pen]-[Gly(Allyl)]-T-[W(7-Me)]-[Lys(Ac)]-[Pen]- [Tyr(O-Al!yl)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pa!]-[Sarc]- NH2	0.0285
288	Ac-[Pen]-[Gly(Allyl)]-D-[W(7-Me)]-[Lys(Ac)HPen]- [Tyr(O-Allyl)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]nh2	0.062
289	Ac-[Pen]-[Gly(Allyp]-T-(W(4-F)]-[Lys(Ac)]-[Pen]-[Tyr(OA1 ly 1)] -[2-Nal ] - [THP]-[Lys(Ac)] -N- [3Pal]-[ Sarc]-NH2	0.059

2ll

SEQ ID No. / Peptide No.	Sequence*	pStat3 IITRF (uM)	PBNIC pSTAT3 (nM)
290	Ac-[Pen]-N-D- [W(7-Me)]- [Ly s(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nall-[THP]-E-N-[3Pal]-[Sarc]-NH2	0.033
291	Ac-[Pen]-L-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2- aminoethoxy)]-[2-Nal]-[TI-IP]-E-N-[3Pal]-[Sarc]-NH2	0.0318
299	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4- CONH2)]-[2-Nal]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]nh2	0.0442
308	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-F-[2-Nal][THP]-[Lys(Ac)]-N-[3Pal ] -[ Sarc]-NH2	0.0298
309	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[(D)Tyr]-[2- Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2	0.0618
310	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)HPen]-[Phe(4-OMe)]- [2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2	0.0438
311	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4- CONH2)]-[2-Nal]-[THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2	0.0319
332	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(N-acetyl-N-propyl)]-[Pen]Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]nh2	0.0449
333	Ac-[Pen] -N-T- [ W(7-Me)] - [Ly s(N-acety l-N-buty l )]-[ Pen] Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]nh2	0.0494
334	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(N-acetyl-N-isobutyl)][Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH2	0.05] 6
335	Ac-[Pen]-N-T-[W(7-Me)]-[Lys(N-acetyl-N-benzyl)]-[Pen]Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]nh2	0.0447
339	Ac-[Pen]-L-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4- CONH2)]-[2-Nal]-[aMeLeu]-E-N-[3Pal]-[Sarc]-NH2	0.0399
347	Ac-[Pen]-L-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-OMe)]- [2-Nal]-[aMeLeu]-E-N-[3Pal]-[Sarc]-NH2	0.0459
373	Ac-[Abu]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2	0.0412

EXAMPLE 3: NK CELL BASED ASSAY

[00489] Natural killer (NK) cells, purified from human peripheral blood of healthy donors by négative sélection (Miltenyi Biotech, Cat# 130-092-657), were cultured in complété media (RPMI 5 1640 containing 1O%FBS, L-glutamine and penicillin-streptomycin) in the presence of IL-2 (RnD,

Cat # 202-1L-010/CF) at 25 ng/mL. After 7 days, cells were centrifuged, and resuspended in complété media at 1E6 cells/mL. Recombinant IL-23 at predetermined ECso to EC75 and IL-18 (RnD, Cat # B003-5) at 10 ng/mL were mixed with varying concentrations of peptides, and added to NK cells seeded at 1E5 cells per well. After 20 to 24 hours, IFNy in the supernatant was

212 quantifiée! using Quantikine EL1SA (RnD, Cat # DIF50). IC50 values determîned from these data are shown in Table E2A and Table E2B. Where not shown (N/A), data was not yet determîned.

Table E2. ICso of Illustrative Peptide Inhibitors in Primary Cell Line (NK Cell Assay)

SEQ ID No. / Peptide No.	NK Cell Assay (nM)
1	N/A
2	2.11
3	2.05
4	5.81
5	0.785
6	2.46
7	2.62
8	N/A
9	N/A
10	N/A
11	1.73
12	1.91
13	2.37
14	2.8
15	0.963
16	0.779
17	2.63
18	6.52
19	N/A
20	2.88
21	2,04
22	0.774
23	0.706
24	N/A
25	N/A
26	0.587
27	N/A
28	N/A
29	N/A
30	0.896
31	N/A
32	1.3
33	1.32
34	N/A
35	N/A
36	N/A
37	N/A
38	N/A

213

SEQ ID No. / Peptide No.	NK Cell Assay (nM)
39	34.1
40	N/A
41	1.51
42	N/A
43	N/A
44	N/A
45	N/A
46	1.39
47	1.7
48	1.01
49	N/A
50	N/A
51	0.627
52	0.46
53	0.812
54	1.64
55	1.14
56	4.33
57	1.68
58	N/A
59	1.68
60	0.973
61	2.23
62	2.1
63	28.1
64	1.42
65	1.8
66	0.878
67	0.771
68	1.07
69	9.99
70	N/A
71	2.88
72	1.81
73	8.1
74	1.82
75	1.84
78	256
79	2.68
80	0.0515
81	N/A
82	N/A
83	N/A

214

SEQ ID No. ! Peptide No.	NK Cell Assay (nM)
84	N/A
85	N/A
86	N/A
87	N/A
88	N/A
89	N/A
90	N/A
91	N/A
92	N/A
93	N/A
94	N/A
95	N/A
96	N/A
97	N/A
98	N/A
99	N/A
100	N/A
101	N/A
102	N/A
103	0.0277
104	0.0192
105	0.0523
106	0.0325
107	N/A
108	N/A
109	N/A
110	N/A
111	N/A
112	N/A
113	N/A
114	N/A
115	N/A
116	N/A
117	0.0281
118	N/A
119	N/A
120	0.0512
121	0.04
122	0.079
123	0.042
124	0.0874
125	0.1
126	N/A

SEQ ID No. ! Peptide No.	NK Ceii Assay (nM)
127	N/A
130	N/A
131	N/A
132	0.0456
133	N/A
134	N/A
135	N/A
136	N/A
137	0.0177
138	N/A
139	N/A
140	N/A
141	N/A
142	N/A
143	N/A
144	N/A
145	N/A
146	N/A
147	N/A
148	0.025
149	N/A
150	N/A
151	N/A
152	N/A
153	N/A
154	N/A
155	0.049
156	N/A
157	N/A
158	0.0258
159	0.0416
160	N/A
161	N/A
162	0.029
163	| N/A

EXAMPLE 4: STABILITY OF PEPTIDE INHIBITORS IN SIMULATED INTESTINAL

FLUID (S1FL SIMULATED GASTRIC FLUID (SGF) AND REDOX CONDITIONS

[00490] Studies were carrîed out in simulated intestinal fluid (SIF) and simulated gastric fluid 5 (SGF) to evaluate gastric stability of the peptide inhîbîtors of the présent invention. In addition, studies were carried out to assess redox stability ofthe peptide inhîbiotrs ofthe présent invention.

216

[00491] SIF was prepared by adding 6.8 g of monobasic potassium phosphate and 10.0 g of pancreatin to 1.0 L of water. After dissolution, the pH was adjusted to 6.8 usmg NaOH. DMSO stocks (2 mM) were first prepared for the test compounds. Aliquots of the DMSO solutions were dosed into 6 individual tubes, each containîng 0.5 mL of SIF, which is pre-warmed to 37°C. The final test compound concentration was 20 μΜ. The vials were kept in a benchtop Thermomixer® for the duration of i:he experiment. At each timepoint (0, 5,10, 20, 40, 60, or 360 minutes or 24 hours), 1.0 mL of acetonitrîle containîng 1% formic acid was added to one vial to terminate the reaction. Samples were stored at 4°C until the end of the experiment. After the final timepoint is sampled, the tubes were mixed and then centrifuged at 3,000 rpm for 10 minutes. Aliquots ofthe supernatant were removed, diluted 1:1 into distilled water containîng internai standard, and analyzed by LCMS/MS. Percent remaining at each timepoint was calculated based on the peak area response ratio of test to compound to internai standard. Time 0 was set to 100%, and ail later timepoînts were calculated relative to time 0. Flalf-lives were calculated by fitting to a fîrst-order exponential decay équation using Graphpad. Stablity in SIF assays is shown in Tables E9 and E10.

[00492] SGF was prepared by adding 20 mg NaCl, 32 mg porcine pepsin (MP Biochemicals, catalog 02102599), and 70μΙ HCl to 10ml water (final pH=2). Aliquots of SGF (0.5ml each) were pre-warmed at 37°C. To start the reaction, 1 μΙ of peptide stock solution (lOmM in DMSO) was added to 0.5ml SGF and thoroughly mixed such that the final peptide concentration was 20μΜ. The reactions were incubated at 37°C with gentle shaking. At each time point (0, 15, 30, 60 min) 50μ 1 aliquots were removed and added to 200 ul acetonitrîle containîng 0.1 % formic acid to quench the reaction. Samples are stored at 4°C until the end of the experiment and centrifuged at 10,000 rpm for 5 minutes. Aliquots ofthe supernatant were removed, diluted 1:1 into distilled water containîng internai standard, and analyzed by LCMS/MS. Percent remaining at each timepoint was calculated based on the peak area response ratio of test to compound to internai standard. Time 0 was set to 100%, and ail later timepoînts were calculated relative to time 0. Half-lives were calculated by fitting to a first-order exponential decay équation using GraphPad. Stability in SGF assays in shown in Table E3.

Table E3. Stability of Illustrative Peptides Inhibitors in Simulated Intestinal Fluid (SIF) and Simulated Gastric Fluid (SGF)

SEQ ID No. / Peptide No.	SGF tl/2 (hr)§	SIF tl/2 (hr) §
1	N/A	22.4

217

SEQ ID No. / Peptide No.	SGFtl/2 (M§	SIF tl/2 (hr) §
2	N/A	>24.0
3	N/A	>24.0
4	N/A	>24.0
5	>24.0	>24.0
6	N/A	>24.0
7	N/A	>24.0
8	N/A	N/A
9	N/A	N/A
10	N/A	N/A
11	N/A	>24.0
12	N/A	>24.0
13	N/A	>24.0
14	N/A	>24.0
15	>24.0	>24.0
16	>24.0	>24.0
17	N/A	6.4
18	N/A	15.1
19	N/A	N/A
20	N/A	>24.0
21	N/A	>24.0
22	>24.0	>24.0
23	>24.0	>24.0
24	N/A	>24.0
25	N/A	>24.0
26	>24.0	20.3
27	N/A	>24.0
28	N/A	>24.0
29	N/A	>24.0

218

SEQ ID No. / Peptide No.	SGF 11/2 (hr) §	SIF t]/2 (hr) §
30	>24.0	>24.0
31	N/A	>24.0
32	N/A	>24.0
33	N/A	>24.0
34	N/A	>24.0
35	N/A	>24.0
36	N/A	>24.0
37	N/A	>24.0
38	N/A	>24.0
39	N/A	>24.0
40	N/A	>24.0
41	N/A	>24.0
42	N/A	>24.0
43	N/A	>24.0
44	N/A	>24.0
45	N/A	>24.0
46	N/A	>24.0
47	>24.0	20.1
48	>24.0	13.9
49	N/A	23.8
50	N/A	>24.0
51	>24.0	>24.0
52	>24.0	>24.0
53	>24.0	21.6
54	>24.0	>24.0
55	N/A	21.4
56	N/A	24.1
57	N/A	>24.0

219

SEQ ID No. 1 Peptide No.	SGFtl/2 (hr) §	SIF t1/2 (hr) §
58	N/A	N/A
59	N/A	>24.0
60	>24.0	>24.0
61	N/A	>24.0
62	N/A	>24.0
63	N/A	>24.0
64	N/A	>24.0
65	N/A	>24.0
66	>24.0	21.8
67	>24.0	>24.0
68	N/A	>24.0
69	N/A	>24.0
70	N/A	>24.0
7]	N/A	>24.0
72	N/A	>24.0
73	N/A	>24.0
74	N/A	14.6
75	N/A	15.4
78	N/A	N/A
79	N/A	0.3
80	>24.0	0.1
81	N/A	11.9
82	N/A	N/A
83	N/A	N/A
84	N/A	N/A
85	N/A	N/A
86	N/A	N/A
87	N/A	N/A

220

SEQ ID No. / Peptide No.	SGF 11/2 (hr) §	SIF tl/2 (hr) §
88	N/A	N/A
89	N/A	N/A
90	N/A	N/A
91	N/A	N/A
92	N/A	N/A
93	N/A	>24.0
94	N/A	>24.0
95	N/A	>24.0
96	N/A	>24.0
97	N/A	6.6
98	N/A	>24.0
99	N/A	10.8
100	N/A	>24.0
101	N/A	>24.0
102	N/A	17.9
103	>24.0	>24.0
104	>24.0	>24.0
105	>24.0	>24.0
106	>24.0	>23.0
107	N/A	20.9
108	N/A	>24.0
109	17	14.1
110	N/A	15
111	N/A	8.5
112	N/A	10
113	N/A	10
114	N/A	10.7
115	N/A	>24.0

221

SEQ ID No. / Peptide No.	SGFtl/2 (hr) §	SIF tl/2 (hr) §
116	N/A	22.5
117	>24.0	>24.0
118	N/A	>24.0
119	N/A	19.6
120	N/A	>24.0
121	N/A	>24.0
122	N/A	>24.0
123	N/A	>24.0
124	N/A	18.5
125	N/A	24.5
126	N/A	>24.0
127	N/A	>24.0
130	N/A	0.2
131	N/A	N/A
132	N/A	>24.0
133	>24.0	13.8
134	>24.0	>24.0
135	>24.0	11.7
136	N/A	N/A
137	>24.0	22.7
138	>24.0	9
139	>24.0	16.4
140	N/A	N/A
141	N/A	N/A
142	>24.0	>24.0
143	>24.0	>24.0
144	>24.0	>24.0
145	>24.0	>24.0

222

SEQ ID No. 1 Peptide No.	SGFtl/2 (hr) §	SIF tl/2 (hr) §
146	>24.0	>24.0
147	N/A	>24.0
148	N/A	>24.0
149	N/A	>24.0
150	N/A	>24.0
151	N/A	>24.0
152	N/A	>24.0

§ the matrix used is 100 fold dilution of standard SIF concentration.

EXAMPLE 5: STABILITY OF PEPTIDE INHIBITORS IN HUMAN AND CYNOMLOGUS (MONKEY) FECES

[00493] Studies were carried out in human or cynomlogus monkey fecal homogenate to evaluate 5 gastrointestinal stability of the peptide inhibitors of the present invention.

[00494] Fecal homogenate (20%) was prepared by adding 4 mL of growth medium (1 liter contains 2 g peptone water powder, 2 g yeast extract, 0.1 g NaCl, 0.04 g KH2PO4, 0.01 g CaCh'6H₂O, 0.01 g MgSO4-7H₂O, 2 mL Tween 80, 0.5 g bile salts, 0.5 g L-cysteine HCl, 2 g NaHCOs, and 10 pL Vitamin K, pH adjusted to 6.8, and sterilized by filtration through a 0.22 pm fîlter) to every gram of feces (pooled freshly collected human or cynomolgus monkey feces). The suspension was vortexed to break up large clumps, and homogenized using a bead mill homogenizer. Centrifuged the homogenate at 2800 x g for 15 min. The supernatant is taken out and used for incubations. DMSO stocks (10 rnM) were first prepared for the test compounds. Incubations were performed in an anaérobie chamber condîtioned at 37°C. Aliquots of the DMSO solutions were dosed into

1.0 mL aliquots of 20% fecal homogenate, which are pre-warmed to 37°C. The final test compound concentration was 20 pM. At each timepoint (0, 20 min, 1,3,6, or 24 hours), 100 pL aliquot of each incubation mixture is taken out and added to separate tubes containing 300 pL of 50% acetonitrile/50% methanol and an internai standard to terminate the reaction. Samples were taken out of the anaérobie chamber and stored at 4°C until the end of the experiment. After the final timepoint is sampled, the tubes were mixed and then centrifuged at 3,000 rpm for 10 minutes. Aliquots of the supernatant were removed, diluted 1:1 into distilied water containing 0.1% formic acid, and analyzed by LC/MS/MS. Percent remaining at each timepoint was calculated based on the peak area response ratio of test to compound to internai standard. Time 0 was set to 100%, and ail later timepoints were calculated relative to time 0. Half-lives were calculated by fitting to

223 a first-order exponential decay équation using Graphpad or Excel. Stablity in fecal homogenate assays îs shown in Tables.

EXAMPLE 6: STABILITY OF PEPTIDE INHIBITORS IN RAT PLASMA

[00495] Peptides of interest (20 μΜ) were incubated with pre-warmed rat plasma (SD rat. mixed 5 genderpooled, EDTA, filtered through 0.22 pm, BioreclamationIVT) at 37°C. Aliquots were taken at various time points up to 24 hours (e.g. 0, 0.25, 1, 3, 6 and 24 hr), and immediately quenched with 4 volumes of organic solvent (acetonitrile/methanol (1:1) and 0.1% formic acid, containing 1 μΜ internai standard). Quenched samples were stored at 4 °C until the end ofthe experîment and centrifuged at 4,000 rpm for 10 minutes. The supematant were diluted 1:1 with deionized water 10 and analyzed using LC-MS. Percentage remaîning at each time point was calculated based on the peak area ratio (analyte over internai standard) relative to the initial level at time zéro. Half-lîves were calculated by fitting to a first-order exponential decay équation using GraphPad.

Table E4. Stability of Illustrative Peptides Inhîbîtors in Human Feces, Monkey Feces. and Rat

Plasma

SEQ ID No. / Peptide No.	11/2: Human Feces anaérobie (hr)	tl/2: Monkey Feces anaérobie (hr)	tl/2: Rat Plasma EDTA (hr)
1	>24.0	>24.0	>24.0
2	>24.0	>24.0	>24.0
3	>24.0	>24.0	10.9
4	>24.0	>24.0	>24.0
5	>24.0	15.8	>24.0
6	>24.0	>24.0	13.9
7	>24.0	>24.0	>24.0
8	N/A	N/A	N/A
9	N/A	N/A	N/A
10	N/A	N/A	N/A
11	>24.0	>24.0	12.5
12	>24.0	>24.0	>24.0
13	>24.0	>24.0	7.6
14	>24.0	>24.0	>24.0
15	>24.0	>24.0	>24.0
16	>24.0	20.8	>24.0
17	24.5	11.1	>24.0
18	>24.0	19.6	>24.0
19	N/A	N/A	N/A
20	>24.0	>24.0	20.6
21	>24.0	22.7	>24.0
22	>24.0	7.6	>24.0

224

SEQ ID No. / Peptide No.	11/2: Human Feces anaérobie (hr)	tl/2: Monkey Feces anaérobie (hr)	tl/2: Rat Plasma EDTA (hr)
23	>24.0	15.8	>24.0
24	>24.0	>24.0	1
25	>24.0	>24.0	>24.0
26	4.4	5.3	>24.0
27	4.4	11.6	>24.0
28	5.6	19.2	1
29	5.7	17.5	22.2
30	7.7	9.6	>24.0
31	5.4	17	>24.0
32	21.1	10.2	>24.0
33	25.7	18.1	>24.0
34	>24.0	>24.0	>24.0
35	>24.0	>24.0	>24.0
36	>24.0	14.8	>24.0
37	>24.0	23.5	>24.0
38	>24.0	>24.0	>24.0
39	23.4	24	>24.0
40	>24.0	19.9	>24.0
41	21.5	15.4	>24.0
42	>24.0	15.7	>24.0
43	23.9	24	>24.0
44	22.7	23.2	>24.0
45	>24.0	18.4	>24.0
46	>24.0	>24.0	>24.0
47	>24.0	>24.0	>24.0
48	>24.0	>24.0	>24.0
49	>24.0	>24.0	>24.0
50	>24.0	24.1	>24.0
51	>24.0	24.6	>24.0
52	>24.0	19.5	>24.0
53	17.7	>24.0	>24.0
54	9.4	14.5	>24.0
55	13	19.5	>24.0
56	7.9	12.6	>24.0
57	>24.0	>24.0	>24.0
58	N/A	N/A	N/A
59	20.7	19.9	>24.0
60	>24.0	21.4	>24.0
61	19.5	15.7	>24.0
62	>24.0	>24.0	>24.0
63	>24.0	>24.0	>24.0

225

SEQ ID No. ! Peptide No.	11 /2: Human Feces anaérobie (hr)	11/2: Monkey Feces anaérobie (hr)	tl/2: Rat Plasma EDTA (hr)
64	13.3	14	>24.0
65	14.7	12.5	>24.0
66	4	4.7	>24.0
67	>24.0	>24.0	>24.0
68	>24.0	>24.0	>24.0
69	>24.0	>24.0	>24.0
70	>24.0	>24.0	>24.0
71	>24.0	>24.0	>24.0
72	>24.0	>24.0	>24.0
73	>24.0	23.2	>24.0
74	6.1	17.5	>24.0
75	7.2	17	16.1
78	N/A	N/A	N/A
79	22.9	19	N/A
80	>18.1	14.8	>24.0
81	17.5	18.3	>24.0
82	N/A	N/A	N/A
83	N/A	N/A	N/A
84	N/A	N/A	N/A
85	N/A	N/A	N/A
86	N/A	N/A	N/A
87	N/A	N/A	N/A
88	N/A	N/A	N/A
89	N/A	N/A	N/A
90	N/A	N/A	N/A
91	N/A	N/A	N/A
92	N/A	N/A	N/A
93	1.3	8.4	N/A
94	1.2	9.9	N/A
95	13.3	17.3	>24.0
96	1.5	8.6	N/A
97	5.1	8	N/A
98	6.8	14.1	N/A
99	2.3	8.8	N/A
100	1.6	5.4	N/A
101	1.8	8.1	N/A
102	1.2	4.2	N/A
103	>24.0	>24.0	>24.0
104	>24.0	>24.0	>24.0
105	>24.0	>24.0	>24.0
106	>24.0	>24.0	>24.0

226

SEQ ID No. / Peptide No.	tl/2: Human Feces anaérobie (hr)	tl/2: Monkey Feces anaérobie (hr)	tl/2: Rat Plasma EDTA (hr)
107	19.7	9	>24.0
108	17.3	12.9	>24.0
109	3	12.6	>24.0
110	10.6	20.1	>24.0
111	2	12.8	N/A
112	10.9	17	>24.0
113	1.1	3.4	N/A
114	0.8	2.7	N/A
115	N/A	N/A	>24.0
116	N/A	N/A	>24.0
117	N/A	N/A	>24.0
118	N/A	N/A	>24.0
119	N/A	N/A	>24.0
120	N/A	N/A	>24.0
121	N/A	N/A	>24.0
122	N/A	N/A	>24.0
123	N/A	N/A	>24.0
124	N/A	N/A	>24.0
125	N/A	N/A	>24.0
126	N/A	N/A	>24.0
127	N/A	N/A	>24.0
I30	N/A	N/A	>24.0
131	N/A	N/A	N/A
132	N/A	N/A	>24.0
133	N/A	N/A	>24.0
134	N/A	N/A	>24.0
135	N/A	N/A	>24.0
136	N/A	N/A	N/A
137	>24.0	>24.0	>24.0
138	>24.0	>24.0	>24.0
139	>24.0	>24.0	>24.0
140	N/A	N/A	N/A
141	N/A	N/A	N/A
142	>24.0	>24.0	>24.0
143	>24.0	>24.0	>24.0
144	>24.0	>24.0	>24.0
145	>24.0	19.3	N/A
146	10.3	14.2	N/A
147	>24.0	>24.0	N/A
148	>24.0	>24.0	N/A
149	>24.0	>24.0	N/A

227

SEQ ID No. 1 Peptide No.	tl/2: Human Feces anaérobie (hr)	tl/2: Monkey Feces anaérobie (hr)	tl/2: Rat Plasma EDTA (hr)
150	>24.0	>24.0	N/A
151	>24.0	>24.0	N/A
152	>24.0	>24.0	N/A

[00496] Ail of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this spécification and/or listed in the Application Data Sheet, are incorporated herein by reference, in 5 their entirety.

[00497] From the foregoing it will be appreciated that, although spécifie embodiments of the invention hâve been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordîngly, the invention is not limited except as by the appended daims.

Claims (23)

1. L A monocyclic peptide inhibitor of an interleukin-23 receptor, or a pharmaceutically acceptable sait thereof, wherein the peptide inhibitor comprises an amino acid sequence of Formula (I):

   X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16 (I) wherein

   X3 is absent or any amino acid;

   X4 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide);

   X5 is Cit, Glu, Gly, substituted Gly, Leu, lie, beta-Ala, Ala, Lys, Asn, Pro, Ser, alphaMeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, Lys(Ac), alpha-MeLys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), Gin, or Asp;

   X6 is Thr, Aib, Asp, Dab, Gly, Pro, Ser, alpha-MeGln, alpha-MeLys, alpha-MeLeu, alpha-MeAsn, alpha-MeThr, alpha-MeSer, or Val;

   X7 is unsubstitutedTrp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

   X8 is Gin, alpha-MeLys, alpha-MeLeu, alpha-MeLys(Ac), beta-homoGln, Cit, Glu, Phe, substituted Phe, Tyr, Asn, Thr, Val, Aib, alpha-MeGln, alpha-MeAsn, Lys(Ac), Dab(Ac), Dap(Ac), homo-Lys(Ac), 1-NaI, 2-Nal, Lys(b-Ala), Lys(Gly), Lys(Benzyl, Ac), Lys(butyl, Ac), Lys(isobutyl,Ac), Lys(propyl,Ac), or Trp;

   X9 is Abu, Cys, (D)Cys, alpha-MeCys, (D)Pen, Pen, or Pen(sulfoxide);

   XI0 is Tyr, or substituted Tyr, unsubstituted Phe, or Phe substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, carboxy, carboxamido, 2aminoethoxy, or 2-acetylaminoethoxy; and

   XI1 is 2-Nal, Phe(2-Me), Phe(3-Me), Phe(4-Me), Phe(3,4-dimethoxy), 2Quin, 3Quin, 1Nal, unsubstituted Trp, or Trp substituted with cyano, halo, alkyl, haloalkyl, hydroxy, or alkoxy;

   X12 îs 4-amino-4-carboxy-tetrahydropyran (THP), Acvc, alpha-MeLys, alpha-MeLeu, alpha-MeArg, alpha-MePhe, alpha-MeLeu, alpha-MeLys, alpha-MeAsn, alphaMeTyr, Ala, cyclohexylAla, Lys, or Aib;

   X13 is any amino acid;

   XI4 is any amino acid;

   and

   229

   i) X15 is any amino acîd other than His, (D)His, substituted or unsubstituted His, 2Pal, 3Pal, or 4Pal; Xl6 is Sarc, aMeLeu, (D)NMeTyr, His, (D)Thr, bAla, Pro, or (D)Pro; and the peptide inhibitor is other than

   Ac-[Abu]-QTWQC-[Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]-NNPGNH₂;

   Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu][Lys(Ac)]-NN-[Sarc]-NH₂;

   Ac-[(D)Arg]-[Abu]-Q-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2Nal]-[a-MeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH₂; or

   Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[Aib]-[bA]-NH₂; or ii) Xl5 is His, (D)His, substituted or unsubstituted His, 2PaI, 3 Pal, 4PaI, 4TriazolAla, or 5Pyal; and Xl6 is absent, (D)aMeTyr, (D)NMeTyr or any amino acid other than THP, substituted or unsubstituted Phe, substituted or unsubstituted (D)Phe, substituted or unsubstituted His, substituted or unsubstituted (D)His, substituted or unsubstituted Trp, substituted or unsubstituted 2-Nal, or N-substituted Asp; and the compound is other than

   Ac-[Pen]-N-T-[W(7-Me))-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nai]-[aMcLys]-[Lys(Ac)]-N-H-NH₂;

   wherein 2Pal is 2-pyridyl substituted alanine, and 3Pal is 3-pyridyl substituted alanine, and 4Pai is 4-pyridyl substituted alanine

   and wherein X4 and X9 form a disulfide bond or a thioether bond; and

   230 wherein the peptide inhibitor inhibits the binding of an interleukin-23 (IL-23) to an IL-23 receptor.
2. 2 .The peptide inhibitor or pharmaceutically acceptable sait thereof of claim l, wherein the peptide inhibitor comprises the structure of Formula (Z):

   R1-X-R2 (Z) wherein

   RI is a hydrogen, Ac, a CI-C6 alkyl, a C6-C12 aryl, a C6-Cl2aryl-Cl-6alkyl, a C1-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing; X is the amino acid sequence of Fonnula (I), (la), (Ib), (le), (Id), or any of Formula (ll)-(XVIIId); and R2 is OH, NH2 or N(H)Me.
3. 3 .The peptide inhibitor or pharmaceutically acceptable sait thereof of claim 2, wherein the peptide inhibitor comprises the structure of Formula (Z’):

   R^l-X3-X4-X5-X6-X7-X8-X9-Xl0-Xl I-X12-X13-X14-X15-X16-R² (Z’) wherein

   R¹ is a hydrogen, Ac, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12aryl-Cl-6alkyl, a Cl-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing; andR² is OH, NH₂ orN(H)Me.
4. 4 .The peptide inhibitor or pharmaceutically acceptable sait thereof of claim 3, wherein the peptide inhibitor comprises the structure of Fonnula (Z’):

   R'-X3-Pen-Asn-X6-X7-X8-Pen-X10-Xl 1-X12-X13-X14-X15-X16-R² (Z’-B) wherein the peptide inhibitor is cyclized via a Pen-Pen disulfide bond.
5. 5 .Thepeptide inhibitor or pharmaceutically acceptable sait thereof of any one of claims 3 to 4, wherein X10 is Phe, Phe[4-(2-aminoethoxy)], Phe[4-(2-acetylaminoethoxy)], or Phe(4CONH₂).
6. 6 .The peptide inhibitor or phannaceutically acceptable sait thereof of any one of claims 3 to 5, wherein the peptide inhibitor comprises the structure of Formula (Z’):

   R'-X3-Pen-Asn-Thr-X7-Lys( Ac)-Pen-[F(4-2ae)]-[2-Nal]-X 12-X13-X14-X 15-X16-R² (Z’-F) (SEQ ID NO:515) wherein F(4-2-ae) is Phe[4-(2-aminoethoxy)], and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond.
7. 7 . The peptide inhibitor or pharmaceutically acceptable sait thereof of any one of claims3 to 6, wherein the peptide inhibitor comprises the structure of Formula (Z’):

   231

   R'-X3-Pen-Asn-Thr-X7-Lys(Ac)-Pen-[F(4-2ae)]-[2-Nal]-THP-Glu-Asn-Xl5-Xl6-R² (Z’-I) (SEQ ID NO:5l8) wherein F(4-2-ae) is Phe[4-(2-aminoethoxy)], and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond,
8. 8 . The peptide inhibitor or pharmaceutically acceptable sait thereof of any one of claims3 to

   6,wherein the peptide inhibitor comprises the structure of Formula (Z’): R^l-X3-Pen-Asn-Thr-[W(7-Me)]-Lys(Ac)-Pen-[F(4-2ae)]-[2-Nal]-THP-Glu-Asn-Xl 5X16-R² (Z’-J) wherein F(4-2-ae) is Phe[4-(2-aminoethoxy)], and the peptide inhibitor is cyclized via a Pen-Pen disulfide bond.
9. 9 .Thepeptide inhibitor or pharmaceutically acceptable sait thereof of claim 3, wherein

   X3 is absent or (D)Arg;

   X4 is Abu, Cys, (D)Cys, alpha-MeCys, or Pen;

   X5 îs Ala, (allyl)Gly, Ile, Leu, Asn, Nie, or Gin;

   X6 is Asp, or Thr;

   X7 is (7-methyl)Trp, (4-F)Trp, or Trp;

   X8 is Cit, Lys(Ac), Lys(Benzyl, Ac), Lys(butyl, Ac), Lys(isobutyl,Ac), Lys(propyl,Ac),Gln, 4-adamantyl-Phe, (4-AcNH)Phe, or Tyr;

   X9 is Cys, alpha-MeCys, or Pen;

   XI0 is Phe or substituted Phe, Tyr or substituted Tyr;

   XI l is 2-Nal;

   X12 is 4-amino-4-carboxy-tetrahydropyran (THP), Acpx, Acvc, alpha-MeLys, or aiphaMeLeu;

   Xl3 is alpha-methylGlu, Glu, or Lys(Ac); and

   Xl4 is Asn.
10. 10. A peptideinhibitorof an interleukin-23 receptor, wherein the peptide inhibitor comprises or is any one of the amino acid sequence set forth in any of Table El A and Table El B; or a pharmaceutically acceptable sait thereof.
11. 11. The peptide inhibitor of claim 10,wherein the peptide inhibitor comprises or is any one of the amino acid sequence listed below:

    Ac-[(D) Arg]-[Abu]-Q-T-[W( 7-Ph)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal ][a-MeLysHLys(Ac)]-N-dK-[Sarc]-NH2 (SEQ ID NO:1);

    232

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[aMeLys]-[Lys(Ac)]-N-[(D)Leu)]-[Sarc]-NH2 (SEQ ID NO:2);

    Ac-[Pen]-N-T-[W(7-Me)]'[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[THP]-EN-[(D)Lys]-[Sarc]-NH2 (SEQ ID NO:3);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Qum]-[aMeLys]-[Lys(Ac)]-N-[(D)His]-[Sarc]-NH2 (SEQ ID NO:4);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[aMeLys]-[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:5);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[THP]-EN-[(D)Leu)]-[Sarc]-NH2 (SEQ ID NO:6);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3-Quin]-[aMeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2 (SEQ ID NO:7);

    Ac-[(D)Arg]-[Abu]-Q-T-W-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-NalHTHP]-E-N-N[(D)NMeTyr]-NH2 (SEQ ID NO:8);

    Ac-[(D)Arg]-[Pen]-Q-T-W-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-N[(D)NMeTyr]-NH2 (SEQ ID NO:9);

    Ac-[(D)Ai'g]-[Pen]-Q-T-W-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[aMeG1u]N-F-[(D)NMeTyr]-NH2 (SEQ ID NO: 10);

    Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-ammoethoxy)]-[3Quin]-[THP]-EN-[(D)Lys]-[Sarc]-NH2 (SEQ ID NO:11);

    Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[aMeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2 (SEQ ID NO: 12);

    Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Peii]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-EN-[(D)Leu]-[Sarc]-NH2 (SEQ ID NO: 13);

    Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[aMeLys]-[Lys(Ac)]-N-[(D)Leu]-[Sarc]-NH2 (SEQ ID NO: 14);

    Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-EN-H-[Sarc]-NH2 (SEQ ID NO: 15);

    Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[aMeLys]-[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO: 16);

    Ac-[Abu]-Q-T~[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-NaI]-[aMeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2 (SEQ ID NO: 17);

    233

    Ac-[Abu]-Q-T-[W(7-Ph)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2 (SEQ ID NO:I8);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-[(D)Leu]-[Sarc]-NH2 (SEQ ID NO:20);

    Ac-[Pen]-N-T-[W(7’Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-[(D)Lys]-[Sarc]-NH2 (SEQ ID NO:2l);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-H-[Sarc]-NH2 (SEQ ID NO:22);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Na]]-[aMeLys]-[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:23);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(D)Leu]-[Sarc]-NH2 (SEQ ID NO:24);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-NaI]-[aMeLys]-[Lys(Ac)]-N-[(D)Leu]-[Sarc]-NH2 (SEQ ID NO:25);

    Ac~[Pen]-N-T-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-H-[Sarc]-NH2 (SEQ ID NO:26);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a~ MeLys]-[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:27);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[(D)Leu]-[Sarc]-NH2 (SEQ ID NO:28);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Gly)]-[Pen]-Phe[4-(2-ammoethoxy)]-[2-NaI]-[aMeLys]-[Lys(Ac)]-N-[(D)Leu]-[Sarc]-NH2 (SEQ ID NO:29);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(bAla)HPen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]E-N-H-[Sarc]-NH2 (SEQ ID NO:30);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(bAla)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:31);

    Ac-[Pen]-N-T-[W(7-Et)HLys(Ac)]-[Pen]-Phe[4-(2-ammoethoxy)]-[2-Nal]-[THP]-E-NH-[Sarc]-NH2 (SEQ ID NO:32);

    Ac-[Pen]-N-T-[W(7-Et)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Na]]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:33);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-Et)]-[aMeLys]-[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:34);

    234

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(4-Me)]-[aMeLys]-[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:35);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(6-Me)]-[aMeLvs]-[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:36);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(4-OMe)]-[aMeLys]-[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:37);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-i-Pr)]-[aMeLys]-[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:38);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-nPr)]-[aMeLys]-[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:39);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-OMe)]-[aMeLys]-[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:40);

    Ac-[Pen]-N-T-[W(7-Me)MLys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(6-CI)HaMeLys]-[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:4I);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(5-OMe)]-[aMeLys]-[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:42);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(3-MePh)]-[aMeLys]-[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO;43);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(6-Ph)]-[aMeLys]-[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:44);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(6-Ei)]-[aMeLys]-[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:45);

    Ac-[Pen]-N-T-[W(7-(2-FPh)]- [Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:46);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-[(D)Leu]-[(D)NMeTyr]-NH2 (SEQ ID NO:47);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)J-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-[(D)Lys]-[(D)NMeTyr]-NH2 (SEQ ID NO;48);

    Ac-[Pen]-N~T-[W(7-(2-OMePh)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:49);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[W(7-Ph)]-[aMeLys]-[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:50);

    235

    Ac-[Pen]N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLysJ[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:5l);

    Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-H-[Sarc]-NH2 (SEQ ID NO:52);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-EN-H-[Sarc]-NH2 (SEQ ID NO:53);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ES-H-[Sarc]-NH2 (SEQ ID NO:54);

    Ac-[Pen]-S-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-H-[Sarc]-NH2 (SEQ ID NO:55);

    Ac-[Pen]-S-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ES-H-[Sarc]-NH2 (SEQ ID NO:56);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-H-[(D)NMeTyr]-NH2 (SEQ ID NO:57);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-NaI]-[aMeLys]-[Lys(Ac)]-N-F-[(D)NMeTyr]-NH2 (SEQ ID NO:58);

    Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-ammoethoxy)]-[2-Nal]-[THP]-E-SH-[Sarc]-NH2 (SEQ ID NO:59);

    Ac-[Pen]-S-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)H2-Nal]-[THP]-E-NH-[Sarc]-NH2 (SEQ ID NO:60);

    Ac-[Pen]-S-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoeihoxy)]-[2-Nal]-[THP]-E-SH-[Sarc]-NH2 (SEQ ID NO:6l);

    Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-H-[(D)NMeTyr]-NH2 (SEQ ID NO:62);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E[(D)Asn]-H-[Sarc]-NH2 (SEQ ID NO:63);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EG-H-[Sarc]-NH2 (SEQ ID NO:64);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E[h(Ser)]-H-[Sarc]-NH2 (SEQ ID NO:65);

    Ac-[Pcn]-N-T-[W(7“Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-H-P-NH2 (SEQ ID NO:66);

    236

    Ac-[Pen]-N-T-[W(7-(2-NaI))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]E-N-H-[Sarc]-NH2 (SEQ ID NO:67);

    Ac-[Pen]-N-T-[W(7-3BiPh)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aiTiinoethoxy)]-[2-Nal]-[THP]E-N-H-[Sarc]-NH2 (SEQ ID NO:68);

    Ac-[Pen]-N-T-[W(7-(Phenanthren-5-yl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2Nal]-[THP]-E-N-H-[Sarc]-NH2 (SEQ ID NO:69);

    Ac-[Pen]-N-T-[W(7-(4-Anthracen-5-yl))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2Nal]-[THP]-E-N-H-[Sarc]-NH2 (SEQ ID NO:70);

    Ac-[Pen]-N-T-[W(7-(l-Nal))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]E-N-H-[Sarc]-NH2 (SEQ ID NO:71);

    Ac-[Pen]-N-T-[W(7-(4BiPh))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-H-[Sarc]-NH2 (SEQ ID NO;72);

    Ac-[Pen]-N-T-[W(7-(3,5-t-Bu-Ph))]-[Lys(Ac)KPen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-H-[Sarc]-NH2 (SEQ ID NO:73);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-CONH2)]-[2-NaI]-[THP]-E-N-H[Sarc]-NH2 (SEQ ID NO:74);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-[Phe(4-OMe)]-[2-NaI]-[THP]-E-N-H[Sar<|-NH2 (SEQ ID NO:75);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[3Quin]-[aMeLys]-[Lys(Ac)]-N-[2Pal]-NH2 (SEQ ID NO:78);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-[2Pal]-NH2 (SEQ ID NO:79);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-NaI]-[aMeLys]-[Lys(Ac)]-N-[3Pal]-NH2 (SEQ ID NO:80);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP][Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:8i);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoetlioxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-H-[(D)NMeTyr]-NH2 (SEQ ID NO:82);

    Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][a-MeLys]-E-N-H-[(D)NMeTyr]-NH2 (SEQ ID NO:83);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)HPen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-Phe[4-aminomethyl]-[(D)NMeTyr]-NH2 (SEQ ID NO:84);

    237

    Ac-[Pen]-N-T-[W(7-Me)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLeu][Lys(Ac)]-N-[(D)His]-NH2 (SEQ ID NO:85);

    Ac-[Pen]-N-T-[W(7-iMe)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-[(D)His]-NH2 (SEQ ID NO:86);

    Ac-[(D)ATg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[(D)His]-[(D)NMeTyr]-NH2 (SEQ ID NO:87);

    Ac-[(D)A:rg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-N-[(D)NMeTyr]-NH2 (SEQ ID NO:88);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-N-[(D)NMeTyr]-NH2 (SEQ ID NO:89);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)HPen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-[(D)Val]-[(D)NMeTyr]-NH2 (SEQ ID NO:90);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-[(D)Thr]-[(D)NMeTyr]-NH2 (SEQ ID NO:9l);

    Ac-[(D)Ai*g]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[(D)His]-NH2 (SEQ ID NO:92);

    Ac-[Abu]-N-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-E-N-H[Sarc]-NH2 (SEQ ID NO:93);

    At>[Abu]-N-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[3Quin]-[THP]-E-N-H[Sarc]-NH2 (SEQ ID NO:94);

    Ac-[Abu]-N-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:95);

    Ac-[Abu]-N-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-H[Sarc]-NH2 (SEQ ID NO:96);

    Ac-[Abu]-N-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-amînoethoxy)]-[2-Nai]-[aMeLys]-[Lys(Ac)]-N-H-[Sarc]-NH2 (SEQ ID NO:97);

    Ac-[Abu]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-NaI]-[THP]-EN-H-[Sarc]-NH2 (SEQ ID NO:98);

    Ac-[Abu]-N-T-[W(7-Me)]-[Lys(Ac)]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-NaI]-[THP]-EN-H-[Sarc]-NH2 (SEQ ID NO:99);

    Ac-[(D)Ai-g]-[Abu]-S-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THPlE-N-H-[Sarc]-NH2 (SEQ ID NO: 100);

    238

    Ac-[(D)Arg]-[Abu]-N-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]E-N-[(D)Leu]-[Sarc]-NH2 (SEQ ID NO:l01);

    Ac-[(D)Arg]-[Abu]-N-T-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-amÎnoethoxy)]-[2-Nal][THP]-E-N-H-[Sarc]-NH2 (SEQ ID NO:I02);

    Ac-[Pen]N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO:!03);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Peii]-Phe[4-(2-arninoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH₂(SEQ ID NO:l04);

    Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4*(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3PaI]-[Sarc]-NH2 (SEQ ID NO:l05);

    Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Na]]-[THP]-EN-[3PaI]-[Sarc]-NH2 (SEQ ID NO:l06);

    Ac-[Pen]-N-T-[W(7-Me)]-[CitHPen]-Phe[4-(2-aminoethoxy)M2-NaI]-[THP]-E-N[3Pal]-[Sarc]-NH2 (SEQ ID NO:l07);

    Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-amînoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc|-NH2 (SEQ ID NO:l08);

    Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Pal]-[Sarc]-NH2 (SEQ ID NO: 109);

    Ac-[Abu]~Q-T~[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO:110);

    Ac-[Abu]-Q-T-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Pal]-[Sarc]-NH2 (SEQ ID NO:l 11);

    Ac-[Abu]Q-T-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 112);

    Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Pal]-[bA]-NH2 (SEQ ID NO:113);

    Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-S-[3Pal][bA]-NH2 (SEQ ID NO:114);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[4Pal]-[Sarc]-NH2 (SEQ ID NO:115);

    Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[bA]-NH2 (SEQ ID NO: 116);

    239

    Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP][Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO:l 17);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Quin]-[Sarc]-NH2 (SEQ ID NO: 118);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[ 7~Aza-tryptophan]-[Sarc]-NH2 (SEQ ID NO: 119);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-[3Pal]-[(D)NMeTyr]-NH2 (SEQ ID NO:120);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Peri]-Phe[4-(2-ammoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[(D)NMeTyr]-NH2 (SEQ ID NO:121);

    Ac-[Pen]N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys]-[Lys(Ac)]-N-[3Pa]]-[(D)NMeTyr]-NH2 (SEQ ID NO: 122);

    Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[(D)NMeTyr]-NH2 (SEQ ID NO: 123);

    Ac-[Pen]-S-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoeihoxy)]-[2-Nal]-[THP]-ES-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 124);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-ES-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 125);

    Ac-[Pen]-N-T-[W(7-Ph)]-[Cit]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-NaI]-[THP]-E-N[3Pal]-[Sarc]-NH2 (SEQ ID NO: 126);

    Ac-[Pen]-N-T-[W(7-Ph)]-Q-[Pen]-Phe[4-(2-aminoethoxy)H2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH2 (SEQ ID NO: 127);

    Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-[bA]-NH2 (SEQ ID NO: 130);

    Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)H2-Nal]-[THP]-EN-[3Pal]-[bA]-NH2 (SEQ ID NO:131);

    Ac-[Pen]-S-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NO:132);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-amînoethoxy)]-[2-Nal]-[THP][Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO:133);

    Ac-[Abu]-Q-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH2 (SEQ ID NO: 134);

    240

    Ac-[Abu]-Q-T-[W(7-Ph)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 135);

    Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP][Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO:136);

    Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aceylaminoethoxy)]-[2-Nal][THP]-[Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 137);

    Ac-[Pen]-E-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP][Lys(Ac)J-N-[3Pal]-[Sarc]-NH2 (SEQ ID N0:13S);

    Ac-[Pen]-E-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-ainmoethoxy)]-[2-Nal]-[THP][Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 139);

    Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3PaI|-[Sarc]-NH2 (SEQ ID NO: 140);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP][Lys(Ac)]-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 141);

    Ac-[Pen]-N-T-[W(7-(3-carboxamidophenyl))]-[Lys(Ac)]-[Pen]-Phe[4-(2aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 142);

    Ac-[Pen]-N-T-[W(7-pyrimidin-5-y1)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO:143);

    Ac-[Pen]-N-T-[W(7-imidazopyridinyl)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2Nal]-|THP]-E-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 144);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4~(2-aminoethoxy)]-[2-Nal][NMe(Lys)]-[Lys(Ac)]-N-[His_3Me]-NH2 (SEQ ID NO: 145);

    Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[His_3Me]-NH2 (SEQ ID NO: 146);

    Ac-[Pen]-N-T-[W(7-(4Quin))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 147);

    Ac-[Pen]-N-T-[(W(7-(3-pyrazol-l-yI))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO; 148);

    Ac-[Pen]-N-T-[(W(7-(5-Et))]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]E-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 149);

    Ac-[Pen]-N-T-[W(5-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NO:150);

    241

    Ac-[Pen]-N-T-[(W(7-(3-pyrazol-l-yl))]-[Lys(Ac)J-[Pen]-Phe[4-(2-arninoethoxy)]-[2Nal]-[THP]-E-N-[3Pal]-[Sarc]-NH2 (SEQ IDNO:ï5l);

    Ac-[Pen]-N-T-[W(7-indazol-5-yl)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 152);

    Ac-[Pen]-N-T-[W(4-F)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Pal|-[Sarc]-NH2 (SEQ ID NO:153);

    Ac-[Pen]-N-T-[W(5-CN)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NO:1 54);

    Ac-[Pen]-N-T-[W(7-CN)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NO; 155);

    Ac-[Pen]-N-T-[W(4-OMe)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]E-N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 156);

    Ac-[Pen]-N-T-[W(4-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NO;157);

    Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH2 (SEQ ID NO; 158);

    Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[Acvc]-E-N-[3Pal][Sarc]-NH2 (SEQ ID NO: 159, 285);

    Ac-[Pen]-N-T-[W(5-Ca)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID NO:160);

    Ac-[Pen]-N-T-[Trp_4Aza]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3Pal]-[Sarc]-NH2 (SEQ ID N0;161);

    Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe|4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH2 (SEQ ID NO: 162);

    Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-[Lys(Ac)]N-[3Pal]-[Sarc]-NH2 (SEQ ID NO: 163);

    Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[(5Pyal)]-NH2 (SEQ ID NO:164);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-NaI]-[a-MeLys]-[Lys(Ac)]-N-[(5Pyal)]-NH2 (SEQ ID NO: 165);

    Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[(l-Me)His]-NH2 (SEQ ID NO: 166);

    242

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[aMeLys][Lys(Ac)]-N-[(l-Me)His]-NH2 (SEQ ID NO:l67); or

    Ac-[Pen]-N -T-[W(7-Me]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nai]-[a-MeLys]-[Lys(Ac)]-N-[3Pal]-[(D)NMeTyr]-NH2 (SEQ ID NO:l68);

    and wherein the peptide inhibitor is cyclized via a Pen-Pen disulfïde bond; or via an Abu-C thioether bond;

    or a phannaceutically acceptable sait thereof.
12. 12. The peptide inhibitor of claim 11, wherein the peptide comprises or is:

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-ammoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pal]-NH2 (SEQ ID NO:80);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Pal]-[Sarc]-NH2 (SEQ ID NO: 104);

    Ac-[Pen]-N-T-[W(7-Me)]-Q-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pal][Sarc]-NH2 (SEQ ID NO: 108);

    Ac-[Abu]-Q-T-[W(7-Me)]-Q-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Na]]-[a-MeLys][Lys(Ac)]-N-[3PaI]-[Sarc]-NH2 (SEQ IDNO:110);

    Ac-[Abu]-Q-T-[W(7-Me)]-[Cit]-[Cys]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[a-MeLys][Lys(Ac)]-N-[3Pai]-[Sarc]-NH2 (SEQ ID NO: 112);

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Quin]-[Sarc]-NH2 (SEQ ID NO:118);

    Ac-[Pen]-S-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-S[3Pal]-[Sarc]-NH2 (SEQ ID NO: 124); or

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-S[3Pal]-[Sarc]-NH2 (SEQ ID NO:125);

    and wherein the peptide inhibitor is cyclized via a Pen-Pen disulfïde bond; or via an Abu-C thioether bond;

    or a pharmaceutically acceptable sait thereof.
13. 13. Thepeptîde inhibitor of daim 11 or 12, wherein the peptide is

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Pal]-[Sarc]-NH₂(SEQ ID NO:104),

    Ac-[Pen]-N-T-[W(7-Ph)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Pal]-[Sarc]-NH₂(SEQ ID NO: 106),

    243

    Ac-[Pen]-N-T-W-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3Pai][Sarc]-NH₂(SEQ ID NOs:l58, 162, 284),

    Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[3Pal]-[Sarc]-NH₂(SEQ ID NOs:247, 266),

    Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[His(3-Me)]-[Sarc]-NH₂(SEQ ID NO:26l), or

    Ac-[(D)Arg]-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[PenJ-Phe[4-(2-aminoethoxy)]-[2-Nal][THP]-E-N-[3Pal]-N(H)Me (SEQ ID NO:267), wherein the peptide inhibitor is cyciized via a Pen-Pen disulfide bond, or a pharmaceutically acceptable sait thereof.
14. 14. Thepeptide inhibitor of claim 13, wherein the peptide is

    Ac-[Pen]-N-T-[W(7-Me)]-[Lys(Ac)]-[Pen]-Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N[3Pal]-[Sarc]-NH2(SEQ ID NO:l04), wherein the peptide inhibitor is cyciized via a Pen-Pen disulfide bond, or a pharmaceutically acceptable sait thereof.
15. 15. A pharmaceutical composition comprisingthe peptide inhibitor or pharmaceutically acceptable sait thereof of any one of daims 1-14, and a pharmaceutically acceptable carrier, excipient, or diluent.
16. 16. The phannaceutical composition of claim 15, further comprisîng an enteric coating.
17. 17. The pharmaceutical composition of daim 16, wherein the enteric coating protects and releases the phannaceutical composition within a subject’s lower gastrointestinal system.

    I8. Useof the peptide inhibitor or peptide inhibitor or pharmaceutically acceptable sait thereof of any one of daims 1-14, in the manufacture of a pharmaceutical composition fortreating an Inflammatory Bowd Disease (IBD), ulcerative colitis, Crolm’s disease, Celiac disease (nontropical Sprue), enteropathy associated with séronégative arthropathies, microscopie colitis, collagenous colitis, éosinophilie gastroenteritis, colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficîency-t, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-F'udlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich Syndrome, pouchitis resulting after proctocolectomy and ileoanal anastomosîs, gastrointestinal cancer, pancreatitis, insulin-dependent diabètes mellitus, mastitis,

    244 cholecystitis. cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, or graft versus host disease in a subject.
18. 19. The use of claim 18, wherein the pharmaceutical composition is formulated to be provided to the subject by an oral, parentéral, intravenous, peritoneal, întradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, nebulization, sublingual, buccal, parentéral, rectal, intraocular, inhalation, topically, vaginal, or topical route of administration.

    2O. The use of claim 18wherein the pharmaceutical composition is for treating Inflammatory Bowel Disease (IBD), ulcerative colitis, or Crohn’s disease, wherein the pharmaceutical composition is provided to the subject orally.
19. 21 .The use of claim 18wherein the pharmaceutical composition is for treating psoriasis, wherein the pharmaceutical composition is provided to the subject orally, topically, parenterally, intravenously, subcutaneously, peritoneal y, or intravenons ly.
20. 22. The peptide inhibitor or peptide inhibitor or pharmaceutically acceptable sait thereof of any one of claims 1-14, or the pharmaceutical composition of any one of daims 15 to 17, for use in the treatment of an Inflammatory Bowel Disease (IBD), ulcerative colitis, Crohn’s disease, Celiac disease (nontropical Sprue), enteropathy associated with séronégative arthropathies, microscopie colitis, collagenous colitis, éosinophilie gastroenteritis, colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficîency-1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich Syndrome, pouchitîs resulting after proctocolectomy and ileoana! anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabètes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, or graft versus host disease in a subject, comprising providing to the subject an effective amount of the peptide inhibitor or peptide inhibitor or pharmaceutically acceptable sait thereof of any one of claims 1-14, or the pharmaceutical composition of any one of claims 15 to 17.
21. 23. The composition for use according to claim 22, wherein the pharmaceutical composition is provided to the subject by an oral, parentéral, intravenous, peritoneal, intradennaî, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, nebulization, sublingual,

    245 buccal, parentéral, rectal, întraocular, inhalation, topîcally, vaginal, or topical route of administration.
22. 24. The composition for use according to claim 22,for treating Inflammatory Bowel Disease (IBD), ulcerative colitis, or Crohn’s disease, wherein the pharmaceutical composition is provided to the subject orally.
23. 25. The composition for use according to claim 22,for treating psoriasis, wherein the pharmaceutical composition is provided to the subject orally, topically, parenterally, intravenously, subcutaneously, peritonealy, or intravenously.