COMPOSITIONS AND METHODS FOR SPECIFIC REGULATION OF PYRUVATE DEHYDROGENASE KINASE

• US 20160130302A1
• Filed: 11/17/2015
• Published: 05/12/2016
• Est. Priority Date: 08/12/2011
• Status: Active Grant

• Current Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Inventors: Mochly-Rosen, Daria, Qvit, Nir, Dziesietnik, Marie-Helene Disatnik
• Granted Patent: US 10,131,691 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68
• CPC Class Codes: C12N 9/12 transferring phosphorus containing groups, e.g. kinases (2.7)
• CPC Class Codes: C12Y 207/11002 [Pyruvate dehydrogenase (acetyl-transferring)] kinase (2.7.11.2)
• CPC Class Codes: C12Y 207/11013 Protein kinase C (2.7.11.13)

Abstract

A peptide composition is provided which specifically inhibits the ability of δ-protein kinase C (δPKC) to phosphorylate pyruvate dehydrogenase kinase (PDK) under ischemic conditions. The peptide composition is useful for treating or reducing tissue damage resulting from ischemia and/or reperfusion.

Claims

1. A therapeutic peptide comprising a δ

PKC-selective modulatory peptide and a carrier peptide,

wherein the modulatory peptide comprises a contiguous core sequence of 5 amino acid residues wherein the contiguous core sequence is at least 60% identical to SEQ ID NO;

1; and

wherein the modulatory peptide is linked to the carrier peptide by a peptide bond.

2. The therapeutic peptide according to claim 1, wherein the modulatory peptide consists of 5 to 20 amino acids.

3. The therapeutic peptide according to claim 1, wherein the contiguous core sequence is at least 80% identical to SEQ ID NO:

1.

4. The therapeutic peptide according to claim 1, further comprising a peptide linker between the modulatory peptide and the carrier peptide.

5. The therapeutic peptide according to claim 1, wherein the linker is selected from the group consisting of 2 to 10 amino acids.

6. The therapeutic peptide according to claim 3, wherein the linker consists of the sequence GSG.

7. The therapeutic peptide according to claim 1, wherein the carrier peptide comprises SEQ ID NO:

52.

8. A pharmaceutical composition comprising the therapeutic peptide according to claim 1 and a pharmaceutically acceptable excipient.

9. A method for treating a subject suffering from ischemic injury to cardiac tissue comprising administering to the subject the therapeutic peptide according to claim 1.

10. A composition comprising a δ

PKC-selective modulatory peptide linked to a carrier peptide,

wherein the δ

PKC-selective modulatory peptide is 5 to 20 amino acids in length and comprises a contiguous core sequence of 5 amino acid residues, wherein the contiguous core sequence is at least 60% identical to SEQ ID NO;

1.

11. The composition according to claim 10, wherein the modulatory peptide is linked to the carrier peptide via a disulfide bond.

12. The composition according to claim 10, wherein the modulatory peptide is 5 to 15 amino acids in length and the contiguous core sequence is at least 80% identical to SEQ ID NO:

1.

13. The composition according to claim 10, wherein the carrier peptide comprises SEQ ID NO:

52.

14. A pharmaceutical composition comprising the therapeutic peptide according to claim 10 and a pharmaceutically acceptable excipient

15. A method for treating a subject suffering from ischemic injury to cardiac tissue comprising administering to the subject the composition according to claim 10.