Heparin-binding peptides

• US 5,877,153 A
• Filed: 06/11/1996
• Issued: 03/02/1999
• Est. Priority Date: 06/11/1996
• Status: Expired due to Term

• Current Assignee: American International Biotechnology, LLC
• Original Assignee: Commonwealth Biotechnologies, Inc. (Mayne Pharma)
• Inventors: Sobel, Michael, Harris, Robert B.
• Primary Examiner(s): Tsang, Cecilia J.
• Assistant Examiner(s): DELACROIX MUIRHEI, CYBILLE
• Application Number:
  US08/660,592
• Time in Patent Office: 994 Days
• Field of Search: 514/13, 530/326
• US Class Current: 514/5.9
• 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 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C07K 14/001 by chemical synthesis
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68

Abstract

The present invention provides heparin antagonist peptides. The heparin-binding peptides of the present invention specifically neutralize heparin'"'"'s conventional anticoagulant properties without causing deleterious hemodynamic side-effects or exacerbation of the proliferative vascular response to injury. More specifically, the heparin-binding compounds of the present invention are short-duration drugs to be used in elective or emergency situations which can safely and specifically neutralize heparin'"'"'s conventional anticoagulant properties without causing deleterious hemodynamic side-effects or exacerbation of the proliferative vascular response to injury.

Claims

1. A heparin-binding molecule comprising the following structure SEQ ID NO.:

1!;

R₁ -Ala-Glu-Ala-Arg-Ala-Arg-Arg-Ala-Ala-Ala-Arg-Ala-Ala-Arg-Arg-Ala-Ala-Arg-Ala-R₂

wherein R₁ is succinyl or acetyl and R₂ is an amide or acid moiety.

2. The heparin binding molecule of claim 1, wherein R₂ is COOH.

3. The heparin binding molecule of claim 1, wherein the amino acids are all D-amino acids.

4. A heparin-binding molecule comprising the following structure SEQ ID NO.:

2!;

R₁ -Ala-Glu-Ala-Arg-Ala-Arg-Arg-Ala-Ala-Ala-Arg-Ala-Ala-Arg-Arg-Ala-R₂

wherein R₁ is succinyl or acetyl and R₂ is an amide or acid moiety.

5. The heparin-binding molecule of claim 4, wherein R₂ is COOH.

6. The heparin binding molecule of claim 4, wherein the amino acids are all D-amino acids.

7. A heparin-binding molecule comprising the following structure SEQ ID NO.:

3!;

R₁ -Ala-Glu-Ala-Ala-Ala-Arg-Arg-Ala-Ala-Ala-Arg-Ala-Ala-Arg-Arg-Ala-R₂

wherein R₁ is succinyl or acetyl and R₂ is an amide or acid moiety.

8. The heparin-binding molecule of claim 7, wherein R₂ is COOH.

9. The heparin binding molecule of claim 7, wherein the amino acids are all D-amino acids.

10. A heparin-binding molecule comprising Bis-Arg Helix #2, wherein R₁ is succinyl or acetyl and R₂ is succinyl or acetyl.

11. The heparin binding molecule of claim 10, wherein the amino acids are all D-amino acids.

12. A heparin-binding molecule comprising Tris-Arg Helix #3, wherein R₁ is succinyl or acetyl, R₂ is succinyl or acetyl, and R₃ is succinyl or acetyl.

13. The heparin binding molecule of claim 12, wherein the amino acids are all D-amino acids.

14. A heparin-binding molecule comprising Tetra-Arg Helix #3, wherein R₁ is succinyl or acetyl, R₂ is succinyl or acetyl, R₃ is succinyl or acetyl, and R₄ is succinyl or acetyl.

15. The heparin binding molecule of claim 14, wherein the amino acids are all D-amino acids.

16. A heparin-binding composition comprising one or more of a heparin-binding peptide selected from the group consisting of

R₁ -Ala-Glu-Ala-Arg-Ala-Arg-Arg-Ala-Ala-Ala-Arg-Ala-Ala-Arg-Arg-Ala-Ala-Arg-Ala-R₂

wherein R₁ is succinyl or acetyl and R₂ is an amide or acid moiety;

R₁ -Ala-Glu-Ala-Arg-Ala-Arg-Arg-Ala-Ala-Ala-Arg-Ala-Ala-Arg-Arg-Ala-R₂ ;

wherein R₁ is succinyl or acetyl and R₂ is an amide or acid moiety;

R₁ -Ala-Glu-Ala-Ala-Ala-Arg-Arg-Ala-Ala-Ala-Arg-Ala-Ala-Arg-Arg-Ala-R₂

wherein R₁ is succinyl or acetyl and R₂ is an amide or acid moiety;

Bis-Arg Helix #2, wherein R₁ is succinyl or acetyl and R₂ is succinyl or acetyl;

Tris-Arg Helix #3, wherein R₁ is succinyl or acetyl, R₂ is succinyl or acetyl, and R₃ is succinyl or acetyl; and

Tetra-Arg Helix #3, wherein R₁ is succinyl or acetyl, R₂ is succinyl or acetyl, R₃ is succinyl or acetyl, and R₄ is succinyl or acetyl; and

a carrier therefor.

17. The composition of claim 16, further comprising insulin.

18. The composition of claim 16, wherein the composition is suitable for topical administration.

19. A method of reducing plasma heparin content in a mammal in need of such treatment comprising administering the heparin-binding composition of claim 16 in an amount which is effective to reduce the mammal'"'"'s plasma heparin levels.

20. A method for reducing the anticoagulant effects of heparin in a mammal in need of such treatment comprising administering the heparin-binding composition of claim 16 in an amount which is effective to reduce the anticoagulant effects of heparin.