WO2012104462A1 - Heptapeptides et leur utilisation pour la régulation de l'hypertension - Google Patents

Heptapeptides et leur utilisation pour la régulation de l'hypertension Download PDF

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Publication number
WO2012104462A1
WO2012104462A1 PCT/ES2012/070055 ES2012070055W WO2012104462A1 WO 2012104462 A1 WO2012104462 A1 WO 2012104462A1 ES 2012070055 W ES2012070055 W ES 2012070055W WO 2012104462 A1 WO2012104462 A1 WO 2012104462A1
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Prior art keywords
heptapeptide
amino acid
pharmaceutical composition
peptides
heptapeptides
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PCT/ES2012/070055
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English (en)
Spanish (es)
Inventor
José F. MARCOS LÓPEZ
Salvador VALLÉS ALVENTOSA
Paloma Manzanares Mir
Pedro RUIZ-GIMENEZ
Germán TORREGROSA BERNABÉ
Enrique ALBORCH DOMÍNGUEZ
Juan B. SALOM SANVALERO
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Consejo Superior de Investigaciones Cientificas CSIC
Fundacion para la Investigacion del Hospital Universitario y Politecnico La Fe de La Comunidad Valenciana
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Consejo Superior de Investigaciones Cientificas CSIC
Fundacion para la Investigacion del Hospital Universitario y Politecnico La Fe de La Comunidad Valenciana
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/15—Peptidyl-dipeptidases (3.4.15)
    • C12Y304/15001—Peptidyl-dipeptidase A (3.4.15.1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/81—Protease inhibitors
    • C07K14/8103—Exopeptidase (E.C. 3.4.11-19) inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/485—Exopeptidases (3.4.11-3.4.19)

Definitions

  • the present invention relates to heptapeptides that are characterized as inhibitors of angiotensin I converting enzyme (RCT). It also refers to the use of heptapeptides for the preparation of a medicament for the reduction of hypertension by inhibition of the activity of ACE.
  • RCT angiotensin I converting enzyme
  • Hypertension is characterized in that the blood pressure is higher than desirable for health. Hypertensive individuals have a higher risk of cardiovascular and cerebrovascular complications, resulting in an increase in mortality prematurely in these subjects (Giles TD 2009. J Clin Hypertens (Greenwich) 1 1 (1 1): 61 1 -4). The reversal of hypertension through changes in lifestyle or drug treatments reduces the risk of heart attack (30-40%) and other coronary problems (20%) and seems to also reduce the incidence of other vascular disorders.
  • renin-angiotensin-aldosterone (SRA) system Since alterations in the renin-angiotensin-aldosterone (SRA) system have been associated with hypertension, antihypertensive medications have been developed that use different components of this system as targets, such as reninna inhibitors, angiotensin converting enzyme inhibitors , angiotensin receptor blockers or aldosterone receptor antagonists (Williams B 2009. J Hypertens 27 (3): S19-26).
  • the angiotensin converting enzyme is a peptidase present in vascular endothelial cells in the lung, kidney and brain that converts angiotensin I into the vasoconstrictor peptide angiotensin li, thus contributing to increasing blood pressure.
  • ACE inhibition for the treatment of hypertension is currently performed using medications, such as captopril whose active substance is hydrochlorothiazide, but they cause effects. Side effects such as dry cough and angioedema.
  • medications such as captopril whose active substance is hydrochlorothiazide
  • Side effects such as dry cough and angioedema.
  • studies have been conducted for the inhibition of ACE with peptides of different sequence and length than the peptides of the present invention.
  • Peptides derived from plant and animal proteins, such as milk, soy or fish, have been used for ACE inhibition.
  • Such peptides can be produced by enzymatic hydrolysis from precursor proteins during food processing and digestion. These peptides can be incorporated into functional foods for the development of health-beneficial products and currently there are various products on the market or in development that contain these bioactive peptides with ACE inhibitory activity. However, clinical trials conducted so far with several of these peptides have not demonstrated a clear beneficial effect in all hypertensive patients ⁇ Engberink MF et al 2008. Hypertension 51 (2): 399-405 and De Leo et al 2009. Curr Pharm Des 15 (31): 3622-43).
  • Tryptophan (W), tyrosine (Y), phenylalanine (F), proline (P), isoleucine (I), alanine (A), leucine (L) have been described as important amino acids for ACE activity inhibition and methionine (M) located last in the carboxy terminal end, while the important amino acids in the penultimate positions are valine (V), isoleucine (I), alanine (A), arginine (R), tyrosine (Y) and phenylalanine (F) ⁇ Cheung HS et al 1980.
  • the present invention relates to heptapeptides with antihypertensive effect and the use of said heptapeptides for the preparation of a pharmaceutical composition to decrease hypertension.
  • the peptides of the invention are inhibitors of angiotensin I converting enzyme (RCT).
  • RCT angiotensin I converting enzyme
  • the ACE inhibitory activity of the peptides of the invention was compared with other peptides described above. It was shown that the antihypertensive activity of heptapeptides is superior to those described above.
  • a first aspect of the invention relates to a heptapeptide consisting of the sequence SEQ ID NO: 1, where the first amino acid is an arginine (R) the second amino acid is a lysine (K), the third amino acid is a tryptophan (W), the fourth amino acid is a histidine (H) or a leucine (L), the fifth amino acid is a phenylalanine (F), the sixth amino acid is a leucine ⁇ ! _) Or a histidine (H) and the seventh amino acid It is a tryptophan (W).
  • heptapeptides of the invention coincide in amino acid sequence in the positions described but vary in the fourth and sixth positions counting from the amino terminal end.
  • a preferred embodiment of the first aspect of the invention relates to a heptapeptide consisting of the sequence SEQ ID NO: 2 where the fourth position amino acid is a histidine (H) and the sixth position amino acid is a leucine (L).
  • another preferred embodiment refers to the heptapeptide consisting of the sequence SEQ ID NO: 3 where the fourth position amino acid is a leucine (L) and the sixth position amino acid is a histidine (H).
  • the variation variable
  • place of variation the amino acid that replaces it
  • the present invention also relates to both dextrogyric steroisomers (D) and levogyric stereoisomers (L), whereby another preferred embodiment of the first aspect of the invention refers to the heptapeptide whose steroisomerism is D and another preferred embodiment refers to the heptapeptide whose stereoisomery is L.
  • stereoisomer in the present invention refers to an optical isomer or enantiomer, that is, in the present invention a heptapeptide of the same molecular form and amino acid sequence but of different structural formula.
  • the stereoisomers D and the stereoisomers L differ in the property of diverting the plane of the polarized light in a different direction, with the stereoisomers D being those which deflect it to the right (dextrogyric isomer) and the isomers L (levogyric isomer) which turn left.
  • the enantiomers that form the proteins are L-isomers but to increase the stability and resistance to degradation by proteases present in biological fluids, in the present invention D-isomers have also been generated.
  • the amino terminal and carboxyl terminal ends of the heptapeptides may or may not be modified.
  • the amino terminal end may be acetylated and the carboxyl terminal end may be amidated following the procedures known to the person skilled in the art, and said modification can be performed in solid phase chemical synthesis.
  • Such modifications favor the stability of the peptides against degradation by proteases but do not affect their biological activity.
  • another preferred embodiment of the first aspect of the invention relates to a heptapeptide where the amino terminal end is acetylated and the carboxyl end is amidated.
  • another preferred embodiment of the first aspect of the invention relates to a heptapeptide consisting of SEQ ID NO: 4.
  • Another preferred embodiment refers to a heptapeptide consisting of SEQ ID NO: 5.
  • modification MOD_RES
  • acetylation refers to acetylation and “amidation” refers to amidation.
  • heptapeptide refers to a peptide consisting of seven amino acids linked by peptide bond. From now on we will refer to the "heptapeptides of the invention” as any of the peptides described in the first aspect of the invention. In this description we will refer to the "natural heptapeptides of the invention” such as the isomeric heptapeptides L since they are those that occur in nature.
  • inhibitor primarily refers to the fact that the heptapeptide inhibits (decreases) the activity of ACE and therefore reduces hypertension.
  • An antihypertensive agent is therefore an agent that decreases hypertension.
  • the angiotensin I converting enzyme (ECA, peptidyl dipeptidase A, BC036375.2, EC 3.4.15.1, "angiotensin converting enzyme” or ACE) refers to the enzyme that uses angiotensin I as a substrate converting it into angiotensin II (which is a vasoconstrictor molecule) and bradykinin (which is a vasodilator molecule), which it converts into a non-functional peptide.
  • the activity of this enzyme increases blood pressure and therefore contributes to hypertension in humans.
  • Hypertension as described in the present invention is a disease of diverse etiology characterized by high blood pressure in the systemic circulation (diastolic ⁇ 90 mm Hg; systolic ⁇ 140 mm Hg;).
  • the peptides of the invention can be obtained by chemical synthesis or by strategies derived from biotechnology.
  • the heptapeptide of the invention could be produced from a polypeptide comprising the heptapeptide of the invention, for example after fragmentation thereof.
  • a second aspect of the invention relates to a polypeptide comprising the heptapeptide of the invention.
  • the natural heptapeptide of the invention, or the polypeptide comprising it could be produced from a nucleic acid that encodes it.
  • a third aspect of the invention relates to a nucleic acid comprising the nucleotide sequence encoding the natural heptapeptides of the invention.
  • the peptide sequence would be encoded by a DNA fragment (deoxyribonucleic acid or DNA) according to the laws of the genetic code. All these procedures are common for all those experts in the area of knowledge of the present invention.
  • DNA genetic constructs encoding sequences of the natural peptides of the invention are also part of the invention.
  • Said genetic construction of DNA would direct the intracellular transcription of the heptapeptide sequence, and comprises at least one of the following types of sequences: a) DNA sequence comprising the nucleotide sequence encoding the natural heptapeptide of the invention for its intracellular transcription and translation; b) a gene expression cassette comprising the DNA sequence defined in a) operably linked to transcription control and optionally translation elements; c) DNA sequence corresponding to a gene expression system or vector comprising the natural heptapeptide coding sequence of the invention defined in a) or the expression cassette defined in b), operably linked to at least one promoter that directs the transcription of said sequence, and with other sequences to regulate its transcription such as, for example, start and end signals, or polyadenylation signal, where preferably the vector is a plasmid.
  • a sixth aspect of the invention relates to the host cell comprising the nucleic acid, the expression cassette or the vector encoding sequences of the natural heptapeptide of the invention, where the cell is preferably a mammalian cell (not belonging to the group of human embryonic or germ cells), insect, fungus (including yeasts) or bacteria.
  • the introduction of said gene constructs can be carried out with the methods known in the state of the art.
  • a seventh aspect of the invention relates to the production process of the natural heptapeptide of the invention which comprises culturing the host cells described in the sixth aspect of the invention and the subsequent purification of the natural peptide of the invention.
  • the heptapeptides of the invention can also be synthesized by chemical synthesis, preferably on a solid phase. In this case, both L and D enantiomers can be produced.
  • the synthesis procedure allows the N-terminal end of the peptides to be acetylated and the C-terminal end amidated, which would not significantly affect the ACE inhibitory activity of said peptides.
  • one aspect of the present invention refers to the use of the heptapeptide of the invention for the preparation of a pharmaceutical composition.
  • Another aspect of the invention relates to the use of the heptapeptide of the invention for the preparation of a pharmaceutical composition for the prevention or treatment of arterial hypertension.
  • composition refers to any substance used for prevention, relief, treatment or cure of diseases. In the context of the present invention it refers to a composition comprising at least the heptapeptides of the invention for the treatment of arterial hypertension, that is, the decrease in hypertension.
  • the pharmaceutical composition of the invention can be used both alone and in combination with other compositions for the treatment of hypertension.
  • Another aspect of the present invention relates to the pharmaceutical composition comprising the heptapeptide of the invention.
  • a preferred embodiment of this aspect of the invention relates to the pharmaceutical composition which further comprises a pharmaceutically acceptable excipient and / or at least one vehicle.
  • Another even more preferred embodiment relates to the pharmaceutical composition which also also comprises at least one other active ingredient.
  • excipient refers to a substance that aids in the absorption of the pharmaceutical composition of the invention, stabilizes said pharmaceutical composition or aids in its preparation in the sense of giving it consistency or providing flavors that make it more pleasant.
  • the excipients could have the function of keeping the ingredients together such as starches, sugars or cellulose, sweetening function, dye function, protection function of the pharmaceutical composition such as to isolate it from air and / or moisture. , filling function of a tablet, capsule or any other form of presentation such as dibasic calcium phosphate, disintegrating function to facilitate the dissolution of the components and their absorption in the intestine, without excluding other types of excipients not mentioned in this paragraph.
  • a “pharmacologically acceptable vehicle” refers to those substances, or combination of substances, known in the pharmaceutical sector, used in the preparation of pharmaceutical forms of administration and includes, but are not limited to, solids, liquids, solvents or surfactants.
  • the carrier can be an inert substance or action analogous to any of the compounds of the present invention.
  • the function of the vehicle is to facilitate the incorporation of the expression product of the invention as well as other compounds, to allow a better dosage and administration or to give consistency and form to the pharmaceutical composition.
  • the presentation form is liquid, the vehicle is the diluent.
  • pharmaceutically acceptable refers to the compound referred to being allowed and evaluated so as not to cause damage to the organisms to which it is administered.
  • the heptapeptides of the invention can be consumed as such, forming part of pharmaceutical compositions or food products.
  • an even more preferred embodiment of the last aspect of the invention refers to the pharmaceutical composition that is presented in a form adapted to oral, parenteral or intradermal administration.
  • the heptapeptide of the invention it is necessary that the amount of said peptide present in the pharmaceutical composition or in the food products containing them be sufficient to exert such action.
  • the composition provided by this invention can be provided by any route of administration, for which said composition will be formulated in the pharmaceutical form appropriate to the route of administration chosen.
  • the amount of the heptapeptide of the invention in said compositions is administered at a therapeutically effective concentration.
  • the term "therapeutically effective concentration” refers to the concentration of the heptapeptides of the invention calculated to produce the desired effect and, in general, will be determined, among other causes, by the characteristics of said heptapeptides and the therapeutic effect to be achieved.
  • Pharmaceutically acceptable adjuvants and vehicles that can be used in said compositions are the vehicles known to those skilled in the art.
  • FIG. 1 Contraction of rabbit carotid artery segments.
  • A effect of potassium chloride (KCI) to check the viability of the segment and the reproducibility of angiotensin-mediated vasoconstriction I (Ang I).
  • B effect of the PIECA50L heptapeptide on contraction induced by angiotensin I. Isometric tension was measured in grams (g) and time in minutes (min).
  • FIG. 1 Decreased systolic blood pressure (SBP) obtained in spontaneously hypertensive rats (SHR).
  • SBP spontaneously hypertensive rats
  • the decrease in SBP in SHR ⁇ "spontaneous hypertensive rats') is shown after oral administration of 1 ml of the saline control (O), 50 mg / Kg of captopril (#), 10 mg / Kg of PIECA32L ( ⁇ ), 10 mg / Kg PIECA50L ( ⁇ ), 10 mg / Kg PIECA52L ( ⁇ ).
  • the data represent the mean ⁇ SEM for a minimum of 5 animals and were subjected to ANOVA one way followed by Dunnett test. * , ** , significantly different with respect to the control at P ⁇ 0.05 and P ⁇ 0.01, respectively.
  • the peptides analyzed and characterized in the present invention were chemically synthesized on a solid phase following standard procedures using the N- (9-fluorenyl) methoxycarbonyl group (Fmoc) for the protection of the amino group of the constituent amino acids (Felds GB et al. 1990. International Journal of Peptide and Protein Research 34: 161-214).
  • the amino-terminal end of the peptides was acetylated (Ac) and the carboxy-terminal end amidated (NH 2 ).
  • the peptides were purified by RP-HPLC (reverse phase high performance liquid chromatography) and their identity was confirmed by MALDI-TOF mass spectrometry. "matrix-assisted laser desorption / ionization time-of-flighf). All these procedures are common for all those experts in the area of knowledge of the present invention.
  • PIECA 32L C SEQ ID NO: 6 Ac-RKWHFW-NH 2 b a PIECA50D unmodified, PIECA52D unmodified and PIECA 50D are, respectively, the dextrorome isomers (D) of unmodified PIECA50L, unmodified PIECA52L and PIECA 50L. Since they have the same amino acid sequence, they also refer to the amino acid sequences of their respective L. isomers.
  • PIECA refers to "ACE activity inhibiting peptide” (it can also refer to the English term “PACEI”, of "ACE inhibitor peptide”).
  • EXAMPLE 2 ACE inhibitory potency on the natural substrate Angiotensin I and Bradykinin
  • the inhibitory capacity of the peptides was determined by measuring by HPLC (high performance liquid chromatography ') Angiotensin II or the Bradykinin fragment 1 -5 resulting from the hydrolysis of the natural substrate Angiotensin I or Bradykinin, (Calbiochem Co,) respectively, based on the method proposed in the literature (Centeno et al 2006.
  • EXAMPLE 4 In vivo tests of the antihypertensive effect after oral administration.
  • the antihypertensive effect of the peptides was evaluated by administering them orally at a dose of 10 mg / kg to spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive (WKY).
  • Figure 2 shows the changes in systolic blood pressure (APAS) in SHR rats at different times after oral administration. It also includes the decrease in SBP observed after administration of 50 mg / kg of captopril (Sigma Chemical Co.) or saline solution.
  • APAS systolic blood pressure
  • the systolic blood pressure (SBP) of the control SHR rats, measured by the tail-cuff method, was 201 ⁇ 2 mm Hg (n 59).
  • SBP systolic blood pressure
  • the oral administration of the peptides described PIECA 50L, PIECA 52L and PIECA 32L at 10 mg / Kg induced a significant reduction in SBP whose evolution over time is shown in Figure 2.
  • Figure 2 the lack of effect of the saline solution and the antihypertensive effect of captopril (50 mg / Kg).
  • EXAMPLE 5 In vivo tests of the antihypertensive effect after intravenous administration. In order to assess the use in vivo of the heptapeptides of the invention, these peptides were injected intravenously into spontaneously hypertensive rats.
  • the assay was carried out by sowing the cells in 96-well plates (25 x 10 3 cells / well) and after 24 h they were placed in Contact with increasing concentrations of peptide After 24 hours of exposure, the cytotoxic effects were measured using the MTT reduction test After washing the cells with PBS buffer (phosphate buffered saline), 100 ⁇ / well of the reagent was added MTT and incubated for 2 h After this time, the supernatant was discarded and the cells were washed with the same buffer. The dye was extracted with DMSO and the OD540 was measured in a microplate reader. The percentage inhibition of reduction MTT po The medium of the succinic enzyme dehydrogenase was calculated in relation to the control without peptide (100% viability).
  • the power of the peptide to reduce cell viability is summarized in Table 5. Although there were significant differences depending on the cell type, the IC50 values were in the mimeolar range, from 0.41 ⁇ 0.07 mM for primary hepatocytes to 1.38 ⁇ 0.06 mM on HeptG2 cells. It should be noted that these cytotoxic concentrations were 1000 times higher than the peptide concentrations necessary to inhibit ECA activity.
  • IC50 defined as the Peptide concentration capable of reducing cell viability by 50%. It was calculated for each trial by non-linear regression of the experimental data. The results are expressed as the mean ⁇ SEM for three repetitions.
  • PIECA 50L (SEQ ID. NO 4) 0.41 ⁇ 0.07 1 .31 ⁇ 0.13 1 .38 ⁇ 0.06

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Abstract

La présente invention concerne des heptapeptides inhibiteurs de l'enzyme de conversion de l'angiotensine (ECA). L'invention concerne également le procédé de production des peptides de l'invention au moyen de stratégies biotechnologiques, l'invention concernant en outre l'acide nucléique, la cassette d'expression et le vecteur qui les codent, ainsi que la cellule hôte qui les comprend. L'invention concerne aussi l'utilisation des peptides pour la prévention et/ou le traitement de l'hypertension ainsi que la composition pharmaceutique qui les comprend.
PCT/ES2012/070055 2011-02-04 2012-01-31 Heptapeptides et leur utilisation pour la régulation de l'hypertension Ceased WO2012104462A1 (fr)

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Cited By (4)

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CN111004308A (zh) * 2019-12-30 2020-04-14 华南理工大学 一种抑制血管紧张素转换酶的七肽及其应用
CN111087446A (zh) * 2019-12-30 2020-05-01 中新国际联合研究院 一种抑制血管紧张素转换酶的十肽及其应用
CN111116712A (zh) * 2019-12-30 2020-05-08 中新国际联合研究院 一种具有ace抑制活性的六肽及其应用
CN118530299A (zh) * 2023-08-25 2024-08-23 广州益养生物科技有限公司 一种三肽、三肽盐或衍生物及其应用

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111004308A (zh) * 2019-12-30 2020-04-14 华南理工大学 一种抑制血管紧张素转换酶的七肽及其应用
CN111087446A (zh) * 2019-12-30 2020-05-01 中新国际联合研究院 一种抑制血管紧张素转换酶的十肽及其应用
CN111116712A (zh) * 2019-12-30 2020-05-08 中新国际联合研究院 一种具有ace抑制活性的六肽及其应用
CN111004308B (zh) * 2019-12-30 2021-06-08 华南理工大学 一种抑制血管紧张素转换酶的七肽及其应用
CN118530299A (zh) * 2023-08-25 2024-08-23 广州益养生物科技有限公司 一种三肽、三肽盐或衍生物及其应用

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ES2387435A1 (es) 2012-09-21

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