Agonists of apolipoprotein a-1 and their use for the treatment of diseases associated with dyslipidemia

 

The invention relates to the field of medical biotechnology. The essence of the invention are peptides and peptide analogues that mimic the structural and pharmacological properties of apolipoprotein (Area-1) of a person. The peptides and peptide analogues represent amino acid sequences and multimeric complexes with lipids, applicable for the treatment of various diseases associated with dyslipidemia. In the invention described pharmaceutical compositions and methods of treatment based simulators, Area-1. The technical result - expanding Arsenal of remedies against dyslipidemia. 8 C. and 44 C.p. f-crystals, 8 ill., 10 table.

Description text in facsimile form (see graphic part).

Claims

1. Agonist apolipoprotein A-I (Apo A-I), comprising (i) a peptide of 14-22 residues or peptide analogue which forms an amphipatic-helix in the presence of lipids and which has the formula (I)

Z1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18,

where X1submitted by Proline (P), alanine/p>X3a leucine (L);

X4- acidic amino acid;

X5a leucine (L) or phenylalanine (F);

X6a leucine (L) or phenylalanine (F);

X7- basic amino acid;

X8- acidic amino acid;

X9a leucine (L) or tryptophan (W);

X10a leucine (L) or tryptophan (W);

X11- acidic amino acid or asparagine (N);

X12- acidic amino acid;

X13a leucine (L), tryptophan (W) or phenylalanine (F);

X14- basic amino acid or leucine (L);

X15- by glutamine (Q) or asparagine (N);

X16- basic amino acid;

X17a leucine (L);

X18- basic amino acid;

Z1- H2N - or RC(O)NH-;

Z2Is-C(O)NRR, -C(O)or or-C(O)HE, or a corresponding salt;

each R independently of one another are-H, C1-C6-alkyl, C1-C6-quinil, C1-C6-quinil,5-C20-aryl, C6-C26-alkarim, 5 to 20 atomic heteroaryl, 6-26-atomic achetercialis or 1-4-amino acid peptide or peptide analog;

each sign "-" between residues Xnindependently of one another denotes an amide linkage, a substituted amide tie the re one and up to eight residues of1- X18deleterows; or (iii) an altered form of structural formula (I) in which at least one of the residues X1- X18according to conservative type is replaced by another residue.

2. Agonist of Area-I under item 1, which shows at least 38% activity by activation of the enzyme LCAT compared to Area-I man.

3. Agonist of Area-I on p. 1 which is an altered form of structural formula (I).

4. Agonist of Area-I on p. 3, in which hydrophobic residues are fixed in accordance with structural formula (I) and at least one non-fixed residue replaced by a conservative type to another residue.

5. Agonist of Area-I on p. 4, in which X1submitted by Proline (P), D-Proline (p), glycine (G), asparagine (N) or alanine (A); X2the alanine (A), leucine (L) or valine (V); X3a leucine (L); X5a leucine (L) or phenylalanine (F); X6a leucine (L) or phenylalanine (F); X9a leucine (L) or tryptophan (W); X10a leucine (L) or tryptophan (W); X13a leucine (L), tryptophan (W) or phenylalanine (F); X17a leucine (L), and at least one of the residues X4, X7, X8, X11X12X14X15X16and X18 is fixed in accordance with the structural formula (I), and at least one non-fixed residue replaced by a conservative type to another residue.

7. Agonist of Area-I on p. 6, in which X4presents aspartic acid (D) or glutamic acid (E);

X7the arginine (R), lysine (K) or ornithine;

X8- aspartic acid (D) or glutamic acid (E);

X11the asparagine (N) or glutamic acid (E);

X12- glutamic acid (E);

X14- lysine (K), arginine (R) or ornithine;

X15- by glutamine (Q) or asparagine (N);

X16- lysine (K), arginine (R) or ornithine;

X18the asparagine (N) or glutamine (Q) and at least one of the residues X1X2, X3, X5, X6, X9, X10X13and X17replaced by conservative type to another residue.

8. Agonist of Area-I on p. 6, in which X3submitted by leucine (L), X6the phenylalanine (F), X9a leucine (L) or tryptophan (W), X10a leucine (L) or tryptophan (W) and at least one of the residues X1, X2X5X13and X17replaced by conservative type to another residue.

9. Agonist of Area-I on p. 5 or 7, in which the replacement ositional form of formula (I).

11. Agonist of Area-I on p. 10, in which one turn of the helix peptide or peptide analogue deleterows.

12. Agonist of Area-I under item 1, which is composed of 18 amino acid peptide or peptide analogue of structural formula (I).

13. Agonist of Area-I on p. 12, in which the symbol "-" between residues denotes the group-C(O)NH-; Z1presents H2N and Z2- - (A)HE, or a corresponding salt.

14. Agonist of Area-I on p. 13, in which X1submitted by Proline (P), alanine (A), glycine (G), asparagine (N) or D-Proline (p); X2the alanine (A), valine (V) or leucine (L);

X3a leucine (L);

X4- aspartic acid (D) or glutamic acid (E);

X5a leucine (L) or phenylalanine (F);

X6a leucine (L) or phenylalanine (F);

X7the arginine (R), lysine (K) or ornithine;

X8- aspartic acid (D) or glutamic acid (E);

X9a leucine (L) or tryptophan (W);

X10a leucine (L) or tryptophan (W);

X11- glutamic acid (E) or asparagine (N);

X12- glutamic acid (E);

X13a leucine (L), tryptophan (W) or phenyl-alanine (F);

X14the arginine (R), lysine (K) or ub>17a leucine (L) and

X18the arginine (R), lysine (K) or ornithine.

15. Agonist of Area-I under item 1, which is selected from the group including

peptide 191 PVLDLLRELLEELKQKLK* (SEQ ID NO 191);

peptide 192 PVLDLFKELLEELKQKLK* (SEQ ID NO 192);

peptide 193 PVLDLFRELLEELKQKLK* (SEQ ID NO 193);

peptide 194 PVLELFRELLEELKQKLK* (SEQ ID NO 194);

peptide 195 PVLELFKELLEELKQKLK* (SEQ ID NO 195);

peptide 196 PVLDLFRELLEELKNKLK* (SEQ ID NO 196);

peptide 197 PLLDLFRELLEELKQKLK* (SEQ ID NO 197);

peptide 198 GVLDLFRELLEELKQKLK* (SEQ ID NO 198);

peptide 199 PVLDLFRELWEELKQKLK* (SEQ ID NO 199);

peptide 200 NVLDLFRELLEELKQKLK* (SEQ ID NO 200);

peptide 201 PLLDLFKELLEELKQKLK* (SEQ ID NO 201);

peptide 202 PALELFKDLLEELRQKLR* (SEQ ID NO 202);

peptide 203 AVLDLFRELLEELKQKLK* (SEQ ID NO 203);

peptide 204 PVLDFFRELLEELKQKLK* (SEQ ID NO 204);

peptide 205 PVLDLFREWLEELKQKLK* (SEQ ID NO 205);

peptide 206 PLLELLKELLEELKQKLK* (SEQ ID NO 206);

peptide 207 PVLELLKELLEELKQKLK* (SEQ ID NO 207);

peptide 208 PALELFKDLLEELRQRLK* (SEQ ID NO 208);

peptide 209 PVLDLFRELLNELLQKLK (SEQ ID NO 209);

peptide 210 PVLDLFRELLEELKQKLK (SEQ ID NO 210);

peptide 211 PVLDLFRELLEELOQOLO* (SEQ ID NO 211);

peptide 212 PVLDLFOELLEELOQOLK* (SEQ ID NO 212);

peptide 213 PALELFKDLLEEFRQRLK* (SEQ ID NO 213);

peptide 214 PVLDLFRELLEELKQKLK* (SEQ ID NO 214);

peptide 215 PVLDLFRELLEEWKQKLK* (SEQ ID NO 215);

peptide 230 PVLELFERLLEDLQKKLK (SEQ ID NO 230);

peptide 231 PVLDLFRELLEKLEQKLK (SEQ ID NO 231);

peptide 232 PLLELFKELLEELKQKLK* (SEQ ID NO 232);

or is blocked by the N-end and / or the end, or unlocked for him the forms.

16. Multimeric of alonelove and which is characterized by the structural formula (II)

or its pharmaceutically acceptable salt,

where independently of each each m=0 or 1;

n=0...10 - integer;

each HH is independently represents a peptide or peptide analogue according to p. 1;

each LL is independently represents a bifunctional linker;

each sign "-" independently denotes a covalent bond.

17. Multimeric agonist, Area-I, which shows at least 38% activity by activation of the enzyme lecithin: cholesterol acyltransferase (LCAT) compared to Area-I human rights and which is characterized by the structural formula (III)

or its pharmaceutically acceptable salt, where each X is independently represented by

where each HH is independently represented by basic peptide of formula (I) or its analogue, or mutated abridged, delegated internal position or completed option as described in the text;

each LL is independently presents a bifunctional linker;

independently each m = 0 or 1;

independently each n = 0...8 - integer;

Nyaand Nybindependently are multifunctional linking component, where ywhat about each yaor yb= 3...8 - integer;

p =0...7 - integer;

each sign “-” independently denotes a covalent bond.

18. Multimeric agonist, Area-I, which shows at least 38% activity by activation of the enzyme LCAT compared to Area-I human rights and which is characterized by the formula (IV) or (V):

or

or its pharmaceutically acceptable salt, where each X is independently represented by

where each HH is independently represented by the peptide or peptide analogue p. 1; each LL is independently - bifunctional linker; each n is independently 0 or 1; each independently m = 0...8 - integer;

R1is-OR or-NRR, where

each R independently represents H, C1-C6-alkyl, C1-C6-alkenyl, C1-C6-quinil,5-C20-aryl, C6-C26-alkarim, 5 to 20 atomic heteroaryl or 6-26-atomic achetercialis.

19. Multimeric agonist, Area-I according to any one of paragraphs.16 to 18, in which the bifunctional linker is cleaved.

20. Multimeric agonist, Area-I according to any one of paragraphs.16 to 18, in which n = 0.

21. Multimeric agonist, Area-I pot the other is a peptide under item 13.

23. Multimeric agonist, Area-1 according to any one of paragraphs.16 to 18, in which each HH is independently from each other is a peptide under item 14.

24. Multimeric agonist, Area-I according to any one of paragraphs.16 to 18, in which each HH is independently from each other is a peptide under item 15.

25. The complex of agonist, Area-I and lipid, including agonist, Area-I and lipid, and the agonist, Area-I is a peptide or peptide analogue p. 1, multimeric agonist, Area-I on p. 16, multimeric agonist, Area-I on p. 17 or multimeric agonist, Area-I on p. 18.

26. The complex of agonist, Area-I and lipid on p. 25, in which the agonist Area-I is a peptide under item 12.

27. The complex of agonist, Area-I and lipid on p. 25, in which the agonist Area-I is a peptide under item 13.

28. The complex of agonist, Area-I and lipid on p. 25, in which the agonist Area-I is a peptide under item 14.

29. The complex of agonist, Area-I and lipid on p. 25, in which the agonist Area-I is a peptide under item 15.

30. The complex of agonist, Area-I and lipid on p. 25, in which the lipid is sphingomyelin.

31. The complex of agonist, Area-I and lipid on p. 25, which is in the form of liofilizirovannogo powder.

32. The complex of agonist, Area-I and lipid on p. 25, which is in the form of a solution.

33. The pharmaceutical composition, the soda is RoA-I is a peptide or peptide analogue p. 1, multimeric agonist, Area-I on p. 16, multimeric agonist, Area-I on p. 17 or multimeric agonist, Area-I on p. 18.

34. Pharmaceutical composition for p. 33, in which the agonist Area-I is a peptide under item 12.

35. Pharmaceutical composition for p. 33, in which the agonist Area-I is a peptide under item 13.

36. Pharmaceutical composition for p. 33, in which the agonist Area-I is a peptide under item 14.

37. Pharmaceutical composition for p. 33, in which the agonist Area-I is a peptide under item 15.

38. The pharmaceutical composition according to any one of paragraphs.33 - 37, in which the agonist Area-I is in the form of a complex with lipid, these complex consists of agonist, Area-I and lipid.

39. The pharmaceutical composition according to p. 38, in which the complex of agonist, Area-I and lipid is in the form of liofilizirovannogo powder.

40. The method of treatment of a subject suffering from a disease associated with dyslipidemia, characterized in that the said method comprises the step of introducing the patient an effective amount of an agonist of Area-I under item 1.

41. The method according to p. 40, wherein the agonist of Area-I is in the form of pharmaceutical compositions, with the said composition comprises an agonist of Area-I and pharmaceutically preemie in the form of a complex of agonist, Area-I and lipid these complex consists of agonist, Area-I and lipid.

43. The method according to p. 40, characterized in that associated with dyslipidemia disease is hypercholesterolemia.

44. The method according to p. 40, characterized in that associated with dyslipidemia disease is cardiovascular disease.

45. The method according to p. 40, characterized in that associated with dyslipidemia disease is atherosclerosis.

46. The method according to p. 40, characterized in that associated with dyslipidemia disease is restenosis.

47. The method according to p. 40, characterized in that associated with dyslipidemia disease is the deficiency of HDL or Area-1.

48. The method according to p. 40, characterized in that associated with dyslipidemia disease is hypertriglyceridemia.

49. The method according to p. 40, characterized in that associated with dyslipidemia disease is metabolic syndrome.

50. The method of treatment of a patient suffering from septic shock, characterized in that the said method comprises the step of introducing such subject an effective amount of an agonist of Area-I under item 1.

51. The method according to p. 40 or 50, characterized in that the said subject is a human.

52. The method according to p. 40 or 50, characterized in that the above is

 

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