Cell-permeant peptide-based inhibitor of kinases

Patent metadata

Field	Value
Publication number	US-9327008-B2
Application number	US-63447609-A
Country	US
Kind code	B2
Filing date	Dec 9, 2009
Priority date	Dec 10, 2008
Publication date	May 3, 2016
Grant date	May 3, 2016

Abstract

The described invention provides kinase inhibiting compositions containing a therapeutic amount of a therapeutic inhibitor peptide that inhibits at least one kinase enzyme, methods for treating an inflammatory disorder whose pathophysiology comprises inflammatory cytokine expression, and methods for treating an inflammatory disorder whose pathophysiology comprises inflammatory cytokine expression using the kinase inhibiting compositions.

First claim

What is claimed is:

1. A method for treating an inflammatory disorder characterized by IL-6 expression induced by IL-1β, TNF-α, or a combination thereof, the method comprising the step of:
administering a kinase inhibiting composition to a subject in need thereof, wherein the kinase inhibiting composition comprises
(a) a therapeutic amount of a therapeutic MK2 kinase inhibitor peptide comprising a protein transduction domain and a therapeutic domain, wherein the therapeutic domain has amino acid sequence KALARQLGVAA [SEQ ID NO: 23]; and
(b) a pharmaceutically acceptable carrier,

wherein the therapeutic amount of the composition is effective
(a) to inhibit an MK2 kinase; and
(b) to reduce expression of IL-6 induced by IL-1β, TNF-α, or a combination thereof, and thereby treat the inflammatory disorder.

2. The method according to claim 1 , wherein the therapeutic inhibitor peptide has the amino acid sequence YARAAARQARAKALARQLGVAA [SEQ ID NO: 11].

3. The method according to claim 1 , wherein the protein transduction domain of the therapeutic inhibitor peptide has substantial identity to the amino acid sequence WLRRIKAWLRRIKA [SEQ ID NO: 31].

4. The method according to claim 1 , wherein the protein transduction domain of the therapeutic inhibitor peptide has the amino acid sequence YARAAARQARA [SEQ ID NO: 5].

5. The method according to claim 1 , wherein the protein transduction domain of the therapeutic inhibitor peptide has substantial identity to the amino acid sequence FAKLAARLYR [SEQ ID NO: 35].

6. The method according to claim 1 , wherein the therapeutic inhibitor peptide has substantial identity to the amino acid sequence FAKLAARLYRKALARQLGVAA [SEQ ID NO: 12].

7. (Withdrawn-previously presented) The method according to claim 1 , wherein the protein transduction domain of the therapeutic inhibitor peptide has substantial identity to the amino acid sequence KAFAKLAARLYR [SEQ ID NO: 36].

8. The method according to claim 1 , wherein the therapeutic inhibitor peptide has substantial identity to the amino acid sequence KAFAKLAARLYRKALARQLGVAA [SEQ ID NO: 15].

9. The method according to claim 1 , wherein the polypeptide comprises at least one variant that consists of one of SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 15 and wherein the peptide inhibits TNF-α expression.

10. The method according to claim 1 , wherein the polypeptide comprises at least one variant that consists of one of SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 15 and wherein the peptide inhibits IL-1β expression.

11. The method according to claim 1 , wherein the polypeptide comprises at least one variant that consists one of SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 15 and wherein the peptide inhibits IL-6 expression.

12. The method according to claim 1 , wherein the kinase enzyme is a mitogen-activated protein kinase-activated protein kinase.

13. The method according to 12 , wherein the kinase enzyme is mitogen-activated protein kinase-activated protein kinase 2.

14. The method according to claim 12 , wherein the kinase enzyme is mitogen-activated protein kinase-activated protein kinase 3.

15. The method according to claim 1 , wherein the kinase enzyme is a Ca 2+ /calmodulin-dependent protein kinase.

16. The method according to claim 1 , wherein the administering step is by implanting a biomedical device, wherein the composition is disposed on or in the device.

17. The method according to claim 1 , wherein the administering step is parenteral administration.

18. The method according to claim 1 , wherein the polypeptide comprises a variant that consists of SEQ ID NO: 11 and wherein the peptide inhibits TNF-α expression.

19. The method according to claim 1 , wherein the polypeptide comprises a variant that is at least 90% identical to SEQ ID NO: 12 and wherein the peptide inhibits TNF-α expression.

20. The method according to claim 1 , wherein the polypeptide comprises a variant that is at least 90% identical to SEQ ID NO: 15 and wherein the peptide inhibits TNF-α expression.

21. The method according to claim 1 , wherein the polypeptide comprises a variant that consists of SEQ ID NO: 11 and wherein the peptide inhibits IL-1β expression.

22. The method according to claim 1 , wherein the polypeptide comprises a variant that is at least 90% identical to SEQ ID NO: 12 and wherein the peptide inhibits IL-1β expression.

23. The method according to claim 1 , wherein the polypeptide comprises a variant that is at least 90% identical to SEQ ID NO: 15 and wherein the peptide inhibits IL-1β expression.

24. The method according to claim 1 , wherein the polypeptide comprises a variant that consists of SEQ ID NO: 11 and wherein the peptide inhibits IL-6expression.

25. The method according to claim 1 , wherein the polypeptide comprises a variant that is at least 90% identical to SEQ ID NO: 12 and wherein the peptide inhibits IL-6 expression.

26. The method according to claim 1 , wherein the polypeptide comprises a variant that is at least 90% identical to SEQ ID NO: 15 and wherein the peptide inhibits IL-6 expression.

27. The method according to claim 1 , wherein the therapeutic inhibitor peptide is synthetic.

28. The method according to claim 1 , wherein the therapeutic inhibitor peptide comprises D-amino acids, L-amino acids, or a combination thereof.

29. The method according to claim 1 , wherein the pharmaceutically acceptable carrier comprises a sterile aqueous solution.

30. The method according to claim 1 , wherein the therapeutic inhibitor peptide is an isolated peptide.

31. The method according to claim 1 , wherein the kinase inhibiting composition further comprises a preservative.

32. The method according to claim 1 , wherein the composition further comprises a unit-dosage or multi-dosage container for the composition.

33. The method according to claim 32 , wherein the container is a sterile vial or an ampule.

34. The method according to claim 1 , wherein the therapeutic domain of the therapeutic inhibitor peptide has substantial identity to the amino acid sequence KALNRQLGVA [SEQ ID NO: 29].

35. The method according to claim 1 , wherein the therapeutic domain of the therapeutic inhibitor peptide has substantial identity to the amino acid sequence KALNRQLAVAA [SEQ ID NO: 27].

36. The method according to claim 1 , wherein the therapeutic inhibitor peptide has substantial identity to the amino acid sequence YARAAARQARAKALNRQLGVA wherein the protein transduction domain of the therapeutic inhibitor peptide has the amino acid sequence YARAAARQARA (SEQ ID NO: 5), and wherein the therapeutic domain of the therapeutic inhibitor peptide has substantial identity to the amino acid sequence KALNRQLGVA (SEQ ID NO: 29).

37. The method according to claim 1 , wherein the therapeutic inhibitor peptide has substantial identity to the amino acid sequence YARAAARQARAKALNRQLAVAA wherein the protein transduction domain of the therapeutic inhibitor peptide has the amino acid sequence YARAAARQARA (SEQ ID NO: 5), and wherein the therapeutic domain of the therapeutic inhibitor peptide has substantial identity to the amino acid sequence KALNRQLGVAA (SEQ ID NO: 27).

Assignees

• Panitch Alyssa
• Seal Brandon
• Purdue Research Foundation

Inventors

• Panitch Alyssa
• Seal Brandon

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/08

  Vasodilators for multiple indications · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title