IP Library › Granted Patent US 7,700,087
Granted Patent B2
US 7,700,087 · App. 10/241,375 · Granted Apr 20, 2010

Compounds and methods to inhibit or augment an inflammatory response

Assignee: Cambridge Enterprise Limited
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Quick Facts
Patent No.
US 7,700,087
App. No.
10/241,375
Granted
Apr 20, 2010
Kind
B2
Abstract

Isolated and purified chemokine peptides, variants, and derivatives thereof, as well as chemokine peptide analogs, are provided. For example, the invention provides peptides of no more than 15 amino acid residues which include chemokine peptide sequences and variants thereof, as well as cyclic reverse derivatives thereof, which inhibit the activity of at least one chemokine.

Claims (42)

1. An isolated and purified peptide consisting of no more than 15 amino acid residues, 10 of which residues consist of Cys-X 1 -Asp-Pro-X 2 -X 3 -X 4 -Trp-X 5 -Gln (SEQ ID NO:114), wherein X 1 is Ala or Leu, wherein X 2 is a basic or acidic residue, X 3 is Gln, Glu or Leu, X 4 is a basic residue if X 2 is a basic residue or X 4 is an acidic residue if X 2 is an acidic residue, and X 5 is Val, Ile or Leu, which sequence inhibits the activity of at least one native chemokine.

2. The peptide of claim 1 wherein the peptide has a substitution at X 1 , X 2 , X 3 , X 4 , or X 5 relative to the corresponding sequence in MCP-1.

3. The peptide of claim 2 wherein X 1 is Leu, X 2 is Ser or Lys, X 3 is Gln, X 4 is Glu, Ser, Lys or Arg, and X 5 is Ile.

4. The peptide of claim 1 which inhibits MCP-1, MIP1-α, IL-8 and SDF1α.

5. The peptide of claim 1 which consists of no more than 11 amino acid residues.

6. The peptide of claim 1 which has a substitution at X 1 , X 2 and X 5 relative to the corresponding sequence in MCP-1.

7. The peptide of claim 1 which has a substitution at X 2 , X 3 and X 4 , or at X 1 , X 2 , or X 5 , relative to the corresponding sequence in MCP-1.

8. The peptide of claim 1 wherein the basic residue is Lys, Arg or His.

9. The peptide of claim 1 wherein the acidic residue is Asp or Glu.

10. The peptide of claim 1 wherein X 1 is Leu, X 2 is Lys, X 3 is Gln, X 4 is Lys, and X 5 is Ile.

11. The peptide of claim 10 which consists of Cys-Leu-Asp-Pro-Lys-Gln-Lys-Trp-Ile-Gln (SEQ ID NO:116).

12. The peptide of claim 1 wherein the 10 residues consist of Cys-Ala-Asp-Pro-Lys-Gln-Lys-Trp-Val-Gln (SEQ ID NO:7) or Cys-Leu-Asp-Pro-Lys-Gln-Lys-Trp-Ile-Gln (SEQ ID NO:116).

13. The peptide of claim 1 wherein the 15 residues include Glu-Ile-Cys-Ala-Asp-Pro-Lys-Gln-Lys-Trp-Val-Gln (SEQ ID NO:1), Cys-Ala-Asp-Pro-Lys-Gln-Lys-Trp-Val-Gln (SEQ ID NO:7), Glu-Ile-Cys-Leu-Asp-Pro-Lys-Gln-Lys-Trp-Ile-Gln (SEQ ID NO:14) or Cys-Leu-Asp-Pro-Lys-Gln-Lys-Trp-Ile-Gln (SEQ ID NO:116).

14. The peptide of claim 1 which consists of Glu-Ile-Cys-Ala-Asp-Pro-Lys-Gln-Lys-Trp-Val-Gln (SEQ ID NO:1), Cys-Ala-Asp-Pro-Lys-Gln-Lys-Trp-Val-Gln (SEQ ID NO:7), Glu-Ile-Cys-Leu-Asp-Pro-Lys-Gln-Lys-Trp-Ile-Gln (SEQ ID NO:14) or Cys-Leu-Asp-Pro-Lys-Gln-Lys-Trp-Ile-Gln (SEQ ID NO:116).

15. A CRD of a peptide consisting of no more than 15 amino acid residues, 10 of which residues consist of Cys-X 1 -Asp-Pro-X 2 -X 3 -X 4 -Trp-X 5 -Gln (SEQ ID NO:114), wherein X 1 is Ala or Leu, wherein X 2 is a basic or acidic residue, X 3 is Gln, Glu or Leu, X 4 is a basic residue if X 2 is a basic residue or X 4 is an acidic residue if X 2 is an acidic residue, and X 5 is Val, Ile or Leu, which sequence inhibits the activity of at least one native chemokine.

16. The CRD of claim 15 which inhibits MCP-1, MIP1-α, IL-8 and SDF1α migration.

17. The CRD of claim 15 wherein X 1 is Leu, X 2 is Ser or Lys, X 3 is Gln, X 4 is Glu, Ser, Lys or Arg, and X 5 is Ile.

18. The CRD of claim 15 wherein the peptide which consists of no more than 11 amino acid residues.

19. The CRD of claim 15 wherein the peptide has a substitution at X 1 , X 2 and X 5 relative to the corresponding sequence in MCP-1.

20. The CRD of claim 15 wherein the peptide has a substitution at X 2 , X 3 and X 4 , or at X 1 , X 2 , or X 5 , relative to the corresponding sequence in MCP-1.

21. The CRD of claim 15 wherein the basic residue is Lys, Arg or His.

22. The CRD of claim 15 wherein the basic residue is Asp or Glu.

23. The CRD of claim 15 wherein X 1 is Leu, X 2 is Lys, X 3 is Gln, X 4 is Lys, and X 5 is Ile.

24. The CRD of claim 15 wherein the 10 residues consist of Cys-Ala-Asp-Pro-Lys-Gln-Lys-Trp-Val-Gln (SEQ ID NO:7) or Cys-Leu-Asp-Pro-Lys-Gln-Lys-Trp-Ile-Gln (SEQ ID NO:116).

25. The CRD of claim 15 wherein the 15 residues include Glu-Ile-Cys-Ala-Asp-Pro-Lys-Gln-Lys-Trp-Val-Gln (SEQ ID NO:1), Cys-Ala-Asp-Pro-Lys-Gln-Lys-Trp-Val-Gln (SEQ ID NO:7), Glu-Ile-Cys-Leu-Asp-Pro-Lys-Gln-Lys-Trp-Ile-Gln (SEQ ID NO:14) or Cys-Leu-Asp-Pro-Lys-Gln-Lys-Trp-Ile-Gln (SEQ ID NO:116).

26. The CRD of claim 15 which consists of Glu-Ile-Cys-Ala-Asp-Pro-Lys-Gln-Lys-Trp-Val-Gln (SEQ ID NO:1), Cys-Ala-Asp-Pro-Lys-Gln-Lys-Trp-Val-Gln (SEQ ID NO:7), Glu-Ile-Cys-Leu-Asp-Pro-Lys-Gln-Lys-Trp-Ile-Gln (SEQ ID NO:14) or Cys-Leu-Asp-Pro-Lys-Gln-Lys-Trp-Ile-Gln (SEQ ID NO:116), cyclized via a Cys residue added at the C-terminus, or added at both the N- and C-termini.

27. A method of inhibiting an activity of at least one chemokine, comprising: contacting mammal cells with an effective amount of the peptide of claim 1 or the CRD of claim 15 .

28. The method of claim 27 wherein the activity is associated with hematopoietic cell recruitment.

29. The method of claim 28 wherein the activity is associated with macrophage recruitment.

30. The method of claim 27 wherein the peptide inhibits the activity of MCP-1, RANTES, MCP-2, MCP-3, MCP-4, eotaxin, MIP1-α, MIP1-β LARC, 1309, HCC-1, TARC or CKβ38.

31. The method of claim 27 wherein the peptide inhibits the activity of IP-10, PF-4, SDF-1, NAP-2, GROα, GROβ, GROγ or ENA78.

32. A method of inhibiting an indication associated with a chemokine-induced activity, comprising: administering to a mammal afflicted with the indication an effective amount of a peptide of a chemokine, or a CRD thereof, which peptide or CRD consists of no more than 15 amino acid residues, 10 of which residues consist of Cys-X 1 -Asp-Pro-X 2 -X 3 -X 4 -Trp-X 5 -Gln (SEQ ID NO:114), wherein X 1 is Ala or Leu, wherein X 2 is a basic or acidic residue, X 3 is Gln, Glu or Leu, X 4 is a basic residue if X 2 is a basic residue or X 4 is an acidic residue if X 2 is an acidic residue, and X 5 is Val, Ile or Leu, which sequence inhibits the activity of at least one native chemokine.

33. The method of claim 32 wherein the indication is associated with hematopoietic cell recruitment.

34. The method of claim 32 wherein the indication is associated with macrophage recruitment.

35. The method of claim 32 wherein the peptide or the CRD thereof inhibits the activity of MCP-1, RANTES, MCP-2, MCP-3, MCP-4, eotaxin, MIP1-α, MIP1-β, LARC, 1309, HCC-1, TARC or CKβ8.

36. The method of claim 32 wherein the peptide or the CRD thereof inhibits the activity of IP-10, PF-4, SDF-1, NAP-2, GROα, GROβ, GROγ or ENA78.

37. The method of claim 27 or 32 wherein the 10 residues consist of Cys-Ala-Asp-Pro-Lys-Gln-Lys-Trp-Val-Gln (SEQ ID NO:7) or Cys-Leu-Asp-Pro-Lys-Gln-Lys-Trp-Ile-Gln (SEQ ID NO:116).

38. The method of claim 27 or 32 wherein the 15 residues include Glu-Ile-Cys-Ala-Asp-Pro-Lys-Gln-Lys-Trp-Val-Gln (SEQ ID NO:1), Cys-Ala-Asp-Pro-Lys-Gln-Lys-Trp-Val-Gln (SEQ ID NO:7), Glu-Ile-Cys-Leu-Asp-Pro-Lys-Gln-Lys-Trp-Ile-Gln (SEQ ID NO:14) or Cys-Leu-Asp-Pro-Lys-Gln-Lys-Trp-Ile-Gln (SEQ ID NO:116).

39. The method of claim 27 or 32 wherein the peptide consists of Glu-Ile-Cys-Ala-Asp-Pro-Lys-Gln-Lys-Trp-Val-Gln (SEQ ID NO:1), Cys-Ala-Asp-Pro-Lys-Gln-Lys-Trp-Val-Gln (SEQ ID NO:7), Glu-Ile-Cys-Leu-Asp-Pro-Lys-Gln-Lys-Trp-Ile-Gln (SEQ ID NO:14) or Cys-Leu-Asp-Pro-Lys-Gln-Lys-Trp-Ile-Gln (SEQ ID NO:116).

40. The method of claim 27 or 32 wherein the 10 residues in the CRD consist of Cys-Ala-Asp-Pro-Lys-Gln-Lys-Trp-Val-Gln (SEQ ID NO:7) or Cys-Leu-Asp-Pro-Lys-Gln-Lys-Trp-Ile-Gln (SEQ ID NO:116).

41. The method of claim 27 or 32 wherein the 15 residues in the CRD include Glu-Ile-Cys-Ala-Asp-Pro-Lys-Gln-Lys-Trp-Val-Gln (SEQ ID NO:1), Cys-Ala-Asp-Pro-Lys-Gln-Lys-Trp-Val-Gln (SEQ ID NO:7), Glu-Ile-Cys-Leu-Asp-Pro-Lys-Gln-Lys-Trp-Ile-Gln (SEQ ID NO:14) or Cys-Leu-Asp-Pro-Lys-Gln-Lys-Trp-Ile-Gln (SEQ ID NO:116).

42. The method of claim 27 or 32 wherein the CRD consists of Glu-Ile-Cys-Ala-Asp-Pro-Lys-Gln-Lys-Trp-Val-Gln (SEQ ID NO:1), Cys-Ala-Asp-Pro-Lys-Gln-Lys-Trp-Val-Gln (SEQ ID NO:7), Glu-Ile-Cys-Leu-Asp-Pro-Lys-Gln-Lys-Trp-Ile-Gln (SEQ ID NO:14) or Cys-Leu-Asp-Pro-Lys-Gln-Lys-Trp-Ile-Gln (SEQ ID NO:116), cyclized via a Cys residue added at the C-terminus, or added at both the N- and C-termini.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 7, 2007
From: CAMBRIDGE UNIVERSITY TECHNICAL SERVICES, LTD.
To: CAMBRIDGE ENTERPRISE LIMITED
Reel/Frame 020083/0261 →
Continuity (3)
Continuation 0915081300 · Sep 11, 1998
Continuation In Part 0892793900 · Sep 11, 1997
Related Publication 20060073114A1 · Apr 6, 2006