PL227285B1 - Application of peptide derivatives of 1-aminalkyl phosphonic acid esters as inhibitors of NS3/4A protease expressed by human virus of viral hepatitis type C (HCV) - Google Patents
Application of peptide derivatives of 1-aminalkyl phosphonic acid esters as inhibitors of NS3/4A protease expressed by human virus of viral hepatitis type C (HCV)Info
- Publication number
- PL227285B1 PL227285B1 PL409663A PL40966314A PL227285B1 PL 227285 B1 PL227285 B1 PL 227285B1 PL 409663 A PL409663 A PL 409663A PL 40966314 A PL40966314 A PL 40966314A PL 227285 B1 PL227285 B1 PL 227285B1
- Authority
- PL
- Poland
- Prior art keywords
- inhibitors
- hcv
- acid esters
- peptide derivatives
- protease expressed
- Prior art date
Links
- 108091005804 Peptidases Proteins 0.000 title claims abstract description 17
- 239000004365 Protease Substances 0.000 title claims abstract description 16
- 239000003112 inhibitor Substances 0.000 title claims abstract description 12
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 title claims abstract 3
- 108090000765 processed proteins & peptides Proteins 0.000 title abstract description 7
- 241000700605 Viruses Species 0.000 title abstract description 5
- 206010019799 Hepatitis viral Diseases 0.000 title abstract 2
- 201000001862 viral hepatitis Diseases 0.000 title abstract 2
- 150000003008 phosphonic acid esters Chemical class 0.000 title 1
- 239000002253 acid Substances 0.000 claims abstract description 11
- 241000711549 Hepacivirus C Species 0.000 claims description 18
- 150000002148 esters Chemical class 0.000 claims description 10
- VUYWLCHFKCFCNH-QWRGUYRKSA-N (2s)-1-[(2s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoyl]pyrrolidine-2-carboxylic acid Chemical group CC(C)(C)OC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(O)=O VUYWLCHFKCFCNH-QWRGUYRKSA-N 0.000 claims description 4
- XWUSALIIUZARQE-UHFFFAOYSA-N 1,1,2,2-tetrafluoropropane Chemical group CC(F)(F)C(F)F XWUSALIIUZARQE-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 230000005764 inhibitory process Effects 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 4
- 238000002560 therapeutic procedure Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000011282 treatment Methods 0.000 abstract description 2
- 150000007513 acids Chemical class 0.000 abstract 1
- 238000001647 drug administration Methods 0.000 abstract 1
- 230000002427 irreversible effect Effects 0.000 abstract 1
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 abstract 1
- 238000011321 prophylaxis Methods 0.000 abstract 1
- 102000035195 Peptidases Human genes 0.000 description 14
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- -1 O-methyl group Substances 0.000 description 2
- 108010022999 Serine Proteases Proteins 0.000 description 2
- 102000012479 Serine Proteases Human genes 0.000 description 2
- 208000010710 hepatitis C virus infection Diseases 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000002797 proteolythic effect Effects 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- LKDMKWNDBAVNQZ-UHFFFAOYSA-N 4-[[1-[[1-[2-[[1-(4-nitroanilino)-1-oxo-3-phenylpropan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)NC(C)C(=O)NC(C)C(=O)N1CCCC1C(=O)NC(C(=O)NC=1C=CC(=CC=1)[N+]([O-])=O)CC1=CC=CC=C1 LKDMKWNDBAVNQZ-UHFFFAOYSA-N 0.000 description 1
- WCKQPPQRFNHPRJ-UHFFFAOYSA-N 4-[[4-(dimethylamino)phenyl]diazenyl]benzoic acid Chemical compound C1=CC(N(C)C)=CC=C1N=NC1=CC=C(C(O)=O)C=C1 WCKQPPQRFNHPRJ-UHFFFAOYSA-N 0.000 description 1
- SJQRQOKXQKVJGJ-UHFFFAOYSA-N 5-(2-aminoethylamino)naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(NCCN)=CC=CC2=C1S(O)(=O)=O SJQRQOKXQKVJGJ-UHFFFAOYSA-N 0.000 description 1
- 108090000617 Cathepsin G Proteins 0.000 description 1
- 102000004173 Cathepsin G Human genes 0.000 description 1
- 108090000317 Chymotrypsin Proteins 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 238000005862 Oleksyszyn synthesis reaction Methods 0.000 description 1
- 108010067372 Pancreatic elastase Proteins 0.000 description 1
- 102000016387 Pancreatic elastase Human genes 0.000 description 1
- 108010033276 Peptide Fragments Proteins 0.000 description 1
- 102000007079 Peptide Fragments Human genes 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960000517 boceprevir Drugs 0.000 description 1
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 230000003448 neutrophilic effect Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- 229960002935 telaprevir Drugs 0.000 description 1
- 108010017101 telaprevir Proteins 0.000 description 1
- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 229960004854 viral vaccine Drugs 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Opis wynalazkuDescription of the invention
Przedmiotem wynalazku jest zastosowanie peptydowych pochodnych estrów kwasów 1-aminoalkilofosfonowych jako inhibitorów proteazy NS3/4A ekspresjonowanej przez ludzki wirus zapalenia wątroby typu C (HCV).The present invention relates to the use of peptide derivatives of 1-aminoalkylphosphonic acid esters as inhibitors of the NS3 / 4A protease expressed by the human hepatitis C virus (HCV).
Aktualnie na świecie ponad 150 milionów ludzi zarażonych jest wirusem HCV. Szczególnie istotnym jest fakt, iż każdego roku notuje się ponad 350 tysięcy zgonów na skutek powikłań oraz chorób towarzyszących infekcjom wirusa zapalenia wątroby typu C. Szacuje się, iż w Polsce liczba osób zarażonych wirusem HCV wynosi około 700 tysięcy. Niestety, wysoka zdolność wirusa HCV do mutowania własnego materiału genetycznego utrudnia opracowanie skutecznej szczepionki przeciwwirusowej, która pozwoliłaby na jego całkowite wyeliminowanie. Ponadto stosowana do niedawna jedyna skuteczna terapia dwuskładnikowa (składająca się z interferonu i Ribavarinu) często nie była dobrze tolerowana przez pacjentów. Co więcej, pojawiające się nowe genotypy wirusa okazały się być całkowicie oporne na jej działanie. W maju 2011 roku, Amerykańska Agencja ds. Żywności i Leków (FDA) zaakceptowała dwa nowe terapeutyki (Telaprevir, Boceprevir), które stosowane są w leczeniu wirusowego zapalenia wątroby typu C. Mechanizm ich działania oparty jest na hamowaniu aktywności proteolitycznej wirusowej proteazy NS3/4A. Enzym ten pełni kluczową rolę w replikacji wirusa HCV - inhibicja aktywności proteazy NS3/4A nie pozwala na powstanie wirionów zdolnych do dalszej replikacji. Największym problemem związanym z wykorzystaniem inhibitorów proteazy NS3/4A są pojawiające się mutacje materiału genetycznego, dzięki którym wirus uzyskuje oporność na nowe terapeutyki. Z tego też powodu niesłychanie ważnym jest nieustanne poszukiwanie nowych związków będących inhibitorami tej kluczowej dla cyklu życiowego wirusa proteazy (Alkhouri N, Zein NN., Cleve Clin J Med. 2012, 79, 213-22; Pawlotsky, JM., Gastroenterology 2014, 146, 1176-92).Currently, over 150 million people worldwide are infected with HCV. It is particularly important that each year over 350,000 deaths are recorded as a result of complications and diseases accompanying hepatitis C virus infections. It is estimated that in Poland the number of people infected with HCV is approximately 700,000. Unfortunately, the high ability of HCV to mutate its own genetic material makes it difficult to develop an effective antiviral vaccine that would allow its complete elimination. Moreover, the only effective two-component therapy (consisting of interferon and Ribavarin) used until recently was often not well tolerated by patients. Moreover, the emerging new virus genotypes turned out to be completely resistant to its effects. In May 2011, the US Food and Drug Administration (FDA) approved two new therapeutics (Telaprevir, Boceprevir) that are used in the treatment of hepatitis C. Their mechanism of action is based on the inhibition of the proteolytic activity of the viral protease NS3 / 4A. . This enzyme plays a key role in HCV replication - inhibition of NS3 / 4A protease activity prevents the formation of virions capable of further replication. The biggest problem related to the use of NS3 / 4A protease inhibitors are the emerging mutations of the genetic material, thanks to which the virus obtains resistance to new therapeutics. For this reason, it is extremely important to constantly search for new compounds that are inhibitors of this key protease in the life cycle of the virus (Alkhouri N, Zein NN., Cleve Clin J Med. 2012, 79, 213-22; Pawlotsky, JM., Gastroenterology 2014, 146 , 1176-92).
W literaturze naukowej przedstawiono wiele przykładów zastosowania estrów kwasów 1-aminoalkilofosfonowych jako specyficznych inhibitorów proteaz serynowych. Obecny w strukturze inhibitora N-końcowy fragment peptydowy odpowiada za oddziaływanie z kieszeniami S2-Sn proteazy, dzięki czemu możliwe jest uzyskanie wysokiej specyficzności ich działania, tzn. wyeliminowanie możliwości reakcji z innymi proteazami serynowymi, szczególnie inaktywacji ważnych proteaz gospodarza. Natomiast C-końcowy region inhibitora zawiera fosfonowy analog aminokwasu, którego struktura zapewnia nie tylko optymalne oddziaływanie cząsteczki z kieszenią wiążącą S1 proteazy, ale umożliwia aparatowi katalitycznemu enzymu rozpoczęcie nukleofilowego ataku na atom fosforu, co w konsekwencji prowadzi do samobójczej inaktywacji proteazy (Sienczyk, M., Oleksy szyn, J. Curr Med Chem. 2009, 16, 1673).Many examples of the use of 1-aminoalkylphosphonic acid esters as specific inhibitors of serine proteases have been presented in the scientific literature. The N-terminal peptide fragment present in the structure of the inhibitor is responsible for the interaction with the protease S2-Sn pockets, thanks to which it is possible to obtain a high specificity of their action, i.e. eliminate the possibility of reaction with other serine proteases, especially inactivation of important host proteases. On the other hand, the C-terminal region of the inhibitor contains the phosphonic analog of the amino acid, the structure of which not only ensures the optimal interaction of the molecule with the protease S1 binding pocket, but allows the enzyme's catalytic apparatus to initiate a nucleophilic attack on the phosphorus atom, which in turn leads to suicidal inactivation of the protease (Sienczyk, M. , Oleksy szyn, J. Curr Med Chem. 2009, 16, 1673).
W literaturze naukowej i patentowej opisano jedynie zastosowanie peptydowych pochodnych estrów kwasów 1-aminoalkilofosfonowych jako związków hamujących aktywność ludzkich enzymów proteolitycznych takich jak: chymotrypsyna, trypsyna, elastaza neutrofilowa czy katepsyna G (Sieńczyk M., Lesner A., Wysocka M., Legowska A., Pietrusewicz E., Rolka K., Oleksyszyn J., Bioorg Med Chem. 2008, 16, 8863; Winiarski Ł, Oleksyszyn J, Sieńczyk M., J Med Chem. 2012, 55, 6541-53; Pietrusewicz E, Sieńczyk M, Oleksyszyn J. J Enzyme Inhib Med Chem. 2009, 24, 1229-36).The scientific and patent literature describes only the use of peptide derivatives of 1-aminoalkylphosphonic acid esters as compounds inhibiting the activity of human proteolytic enzymes such as chymotrypsin, trypsin, neutrophilic elastase or cathepsin G (Sieńczyk M., Lesner A., Wysocka M., Legowska A. , Pietrusewicz E., Rolka K., Oleksyszyn J., Bioorg Med Chem. 2008, 16, 8863; Winiarski Ł, Oleksyszyn J, Sieńczyk M., J Med Chem. 2012, 55, 6541-53; Pietrusewicz E, Sieńczyk M , Oleksyszyn J. J Enzyme Inhib Med Chem. 2009, 24, 1229-36).
W literaturze patentowej i naukowej nie istnieją doniesienia o zastosowaniu peptydowych pochodnych estrów kwasów 1-aminoalkilofosfonowych jako inhibitorów proteazy NS3/4A ekspresjonowanej przez ludzki wirus zapalenia wątroby typu C (HCV).In the patent and scientific literature there are no reports of the use of peptide derivatives of 1-aminoalkylphosphonic acid esters as inhibitors of the NS3 / 4A protease expressed by the human hepatitis C virus (HCV).
Istotą wynalazku jest zastosowanie estrów kwasów 1-aminoalkilofosfonowych o wzorze ogólnym I w którym W oznacza podstawnik Boc-Val-Pro lub Cbz-Val-Pro, R oznacza pierścień fenylowy podstawiony w pozycji para grupą X, która oznacza: wodór, grupę S-metylową, grupę O-metylową, chlor lub podstawnik 2,2,3,3-tetrafluoropropanowy jako inhibitorów proteazy NS3/4A ekspresjonowanej przez ludzki wirus zapalenia wątroby typu C (HCV).The essence of the invention is the use of 1-aminoalkylphosphonic acid esters of the general formula I in which W is Boc-Val-Pro or Cbz-Val-Pro, R is a phenyl ring substituted in the para position with the X group, which is: hydrogen, S-methyl group , O-methyl group, chlorine or 2,2,3,3-tetrafluoropropane substituent as inhibitors of NS3 / 4A protease expressed by human hepatitis C virus (HCV).
Zastosowanie estrów kwasów 1-aminoalkilofosfonowych o wzorze ogólnym I w którym W oznacza podstawnik Boc-Val-Pro lub Cbz-Val-Pro, R oznacza pierścień fenylowy podstawiony w pozycji para grupą X, która oznacza: wodór, grupę S-metylową, grupę O-metylową, chlor lub podstawnik 2,2,3,3-tetrafluoropropanowy, według wynalazku stanowi nową strategię i alternatywę w zwalczaniu infekcji wirusem ludzkiego zapalenia wątroby typu C.The use of 1-aminoalkylphosphonic acid esters of general formula I in which W is Boc-Val-Pro or Cbz-Val-Pro, R is a phenyl ring substituted in para position with X group which is: hydrogen, S-methyl group, O group -methyl, chlorine or the 2,2,3,3-tetrafluoropropane substituent according to the invention represents a new strategy and alternative in combating human hepatitis C virus infection.
Przedmiot wynalazku przedstawiony jest bliżej w przykładzie, który opisuje aktywność inhibitorową estrów kwasów 1-aminoalkilofosfonowych o wzorze ogólnym I w którym W oznacza podstawnik Boc-ValPro lub Cbz-Val-Pro, R oznacza pierścień fenylowy podstawiony w pozycji para grupą X, która oznacza:The subject of the invention is presented in more detail in the example which describes the inhibitory activity of 1-aminoalkylphosphonic acid esters of the general formula I in which W is Boc-ValPro or Cbz-Val-Pro, R is a phenyl ring substituted in the para position by the X group, which is:
PL 227 285 B1 wodór, grupę S-metylową, grupę O-metylową, chlor lub podstawnik 2,2,3,3-tetrafluoropropanowy wobec proteazy NS3/4A ekspresjonowanej przez ludzki wirus zapalenia wątroby typu C (HCV).Hydrogen, S-methyl, O-methyl, chlorine or a 2,2,3,3-tetrafluoropropane substituent on the NS3 / 4A protease expressed by the human hepatitis C virus (HCV).
Aktywność biologiczną peptydowych pochodnych estrów kwasów 1-aminoalkilofosfonowych o wzorach od II do VII przebadano pod kątem ich zdolności do hamowania proteolitycznej aktywności proteazy NS3/4A ekspresjonowanej przez ludzki wirus zapalenia wątroby typu C. Wszystkie badania przeprowadzono stosując fluorescencyjny substrat (ekstynkcja 350 nm, emisja 460 nm) przy użyciu spektrofluorymetru. Badania obejmowały oznaczenie procentu inhibicji enzymu po 15 min inkubacji z badanym związkiem. Pomiar przeprowadzono w temperaturze 37°C. Pomiaru dokonano przy stałym stężeniu inhibitora (10 μΜ) oraz przy stałym stężeniu enzymu (4,4 nM). W badaniach wykorzystano komercyjnie dostępny substrat Ac-Asp-Glu-Asp(EDANS)-Glu-Glu-Abu-\|/-[COO]-Ala-Ser-Lys(DABCYL)-NH2. Końcowe stężenie substratu wynosiło 1.60 pM. Uzyskane wyniki inhibicji przedstawiono w Tabeli 1.The biological activity of the peptide derivatives of 1-aminoalkylphosphonic acid esters of formulas II to VII was tested for their ability to inhibit the proteolytic activity of the NS3 / 4A protease expressed by the human hepatitis C virus. All studies were performed using a fluorescent substrate (350 nm extinction, 460 emission nm) using a spectrofluorimeter. The tests included determination of the percentage of enzyme inhibition after 15 min incubation with the test compound. The measurement was carried out at 37 ° C. The measurement was performed at a constant inhibitor concentration (10 μΜ) and at a constant enzyme concentration (4.4 nM). The commercially available substrate Ac-Asp-Glu-Asp (EDANS) -Glu-Glu-Abu- \ | / - [COO] -Ala-Ser-Lys (DABCYL) -NH2 was used in the research. Final substrate concentration was 1.60 pM. The inhibition results obtained are presented in Table 1.
Tabela 1. Aktywność inhibitorowa peptydowych pochodnych estrów kwasów 1-aminoalkilofosfonowych- wobec proteazy NS3/4A ekspresjonowanej przez ludzki wirus zapalenia wątroby typu C (HCV).Table 1. Inhibitory activity of peptide derivatives of 1-aminoalkylphosphonic acid esters against NS3 / 4A protease expressed by human hepatitis C virus (HCV).
Claims (1)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL409663A PL227285B1 (en) | 2014-10-02 | 2014-10-02 | Application of peptide derivatives of 1-aminalkyl phosphonic acid esters as inhibitors of NS3/4A protease expressed by human virus of viral hepatitis type C (HCV) |
| PCT/IB2015/054670 WO2016051289A1 (en) | 2014-10-02 | 2015-06-22 | Antiviral pharmaceutical preparation for use in treatment of hepatitis c |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL409663A PL227285B1 (en) | 2014-10-02 | 2014-10-02 | Application of peptide derivatives of 1-aminalkyl phosphonic acid esters as inhibitors of NS3/4A protease expressed by human virus of viral hepatitis type C (HCV) |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| PL409663A1 PL409663A1 (en) | 2015-06-22 |
| PL227285B1 true PL227285B1 (en) | 2017-11-30 |
Family
ID=53396838
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PL409663A PL227285B1 (en) | 2014-10-02 | 2014-10-02 | Application of peptide derivatives of 1-aminalkyl phosphonic acid esters as inhibitors of NS3/4A protease expressed by human virus of viral hepatitis type C (HCV) |
Country Status (2)
| Country | Link |
|---|---|
| PL (1) | PL227285B1 (en) |
| WO (1) | WO2016051289A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RS66213B1 (en) * | 2021-04-16 | 2024-12-31 | Fujian Akeylink Biotechnology Co Ltd | Ring-modified proline short peptide compound and use thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070232527A1 (en) | 2005-06-02 | 2007-10-04 | Anima Ghosal | Medicaments and methods combining a HCV protease inhibitor and an AKR competitor |
| US20120158515A1 (en) | 2010-12-21 | 2012-06-21 | Yahoo! Inc. | Dynamic advertisement serving based on an avatar |
-
2014
- 2014-10-02 PL PL409663A patent/PL227285B1/en unknown
-
2015
- 2015-06-22 WO PCT/IB2015/054670 patent/WO2016051289A1/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| WO2016051289A1 (en) | 2016-04-07 |
| PL409663A1 (en) | 2015-06-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| SG191661A1 (en) | Hcv ns3-ns4a protease inhibition | |
| BRPI0412761A (en) | serine protease inhibitors, particularly vhc protease ns3-ns4a | |
| CA2405043A1 (en) | Inhibitors of serine proteases, particularly hepatitis c virus ns3 protease | |
| JP2006517196A (en) | Composition for treating Flaviviridae viral infection | |
| Martina et al. | Screening of electrophilic compounds yields an aziridinyl peptide as new active-site directed SARS-CoV main protease inhibitor | |
| Lawrenz et al. | Trypstatin as a Novel TMPRSS2 Inhibitor with Broad‐Spectrum Efficacy against Corona and Influenza Viruses | |
| US20170313746A1 (en) | Peptides Useful For Treating Cancer | |
| PL227285B1 (en) | Application of peptide derivatives of 1-aminalkyl phosphonic acid esters as inhibitors of NS3/4A protease expressed by human virus of viral hepatitis type C (HCV) | |
| US20220332683A1 (en) | COMPOSITIONS AND METHODS FOR INHIBITING Mpro and PLpro PROTEASE ACTIVITY AND FOR PREVENTING AND TREATING SARS-CoV-2 INFECTION | |
| JP7233737B2 (en) | Peptides and their use as antiviral agents | |
| Kim et al. | Development of anti-coxsackievirus agents targeting 3C protease | |
| US10869873B2 (en) | Methods and compositions for treating viral diseases | |
| CN114272244A (en) | New application of enretinib or salt thereof | |
| Bose et al. | Camostat in COVID-19 | |
| WO2013178782A1 (en) | Allosteric inhibitors of ns3 protease from hepatitis c virus | |
| Carvaillo et al. | Identification of p-aminobenzylamine derivatives as dual non-covalent inhibitors of the transmembrane host proteases TMPRSS2 and HAT proteases with anti-viral potential | |
| US20190046600A1 (en) | Compositions and uses thereof | |
| MO et al. | Design, synthesis, and resistance patterns of MP-134 and MP-167, two novel inhibitors of HIV type 1 protease | |
| PL229436B1 (en) | Application of the lysine phosphonic analogues and arginine for inhibiting activity of proteolytic protease NS2B/NS3 of West Nole virus | |
| Lawrenz | Discovery and Characterization of Kunitz Inhibitors as Antivirals against Corona and Influenza Viruses | |
| Chow | Towards serine protease inhibitors | |
| Dragovich et al. | Human rhinovirus 3C proteinase | |
| Pattabhi | Exploring RIG-I like receptor signaling: Regulation by DHX15 and RIGing the pathway for broad-spectrum antiviral immunity | |
| McCown et al. | 959 SUBTYPE SPECIFIC RESISTANCE PROFILES AFTER SELECTION OF HCV GENOTYPE 1A OR GENOTYPE 1B REPLICONS WITH TELAPREVIR OR HCV-796 | |
| Conzelmann et al. | Chapter B-Inhibitors for TMPRSS2 to block SARS-CoV-2 infection |