# US 5,352,664 A · Thrombin derived polypeptides; compositions and methods for use

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- Number: US 5,352,664 A
- Document ID: US5352664A
- Status: Granted
- Kind: A
- Application number: 06/925,201
- Filed: 1986-10-31
- Granted: 1994-10-04
- Earliest claimed: 1986-10-31
- Assignees: Board of Regents, The University of Texas System; Monsanto Company
- Inventors: Darrell H. Carney; Kevin C. Glenn
- Web page: https://patentgrep.com/patent/US5352664A

## CPC

- C12N 9/6429: {Thrombin (3.4.21.5)}
- A61P 17/00: Drugs for dermatological disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12Y 304/21005: Thrombin (3.4.21.5)
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12Y: ENZYMES
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Thrombin is now known to mediate a number of potent biological effects on cells bearing high-affinity thrombin receptors. These effects depend, at least in part, upon receptor occupancy signals generated by thrombin's interaction with the high affinity thrombin receptor. The present inventors have formulated synthetic thrombin derivatives capable of selectively stimulating or inhibiting thrombin receptor occupancy signals. The stimulatory thrombin derivatives to bind to cell surface thrombin receptors and stimulate DNA synthesis in cells treated with non-mitogenic concentrations of alpha-thrombin or phorbol myristate acetate. Thus, these peptides, which have both a thrombin receptor binding domain and a segment of amino acids with a sequence common to a number of serine proteases, appear to generate receptor-occupancy dependent mitogenic signals. The inhibitory derivatives, which have no serine esterase conserved amino acid sequences bind to thrombin receptors without generating receptor-occupancy dependent mitogenic signals. This invention describes the peptides and methods for using them to promote cell growth and wound healing or to inhibit scar formation, tissue adhesions, and tumor metastasis and angiogenesis.

## Claims

### Claim 1

A polypeptide consisting essentially of a thrombin receptor binding domain and a serine esterase conserved sequence wherein said polypeptide comprises 23 amino acids.

### Claim 2

A polypeptide thrombin derivative consisting essentially of: Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-Glu-Gly-Asp-Ser-Gl y-Gly-Pro-Phe-Val.

### Claim 3

A polypeptide consisting of the amino acid sequence Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly-Asp-Ala-Cys-Glu-Gly-Asp-Ser-Gl y-Gly-Pro-Phe-Val.

### Claim 4

A composition of matter comprising:
a substantially purified thrombin derivative peptide or physiologically functional equivalent thereof of 23 amino acids in length wherein said peptide includes;
(a) a thrombin receptor binding domain having the sequence Arg-Gly-Asp-Ala; and
(b) a serine esterase conserved sequence;
and wherein the Asp-Ala of the thrombin receptor binding domain comprise the first two amino acids of the serine esterase conserved sequence.

### Claim 5 (depends on 4)

The composition of claim 4 wherein the serine esterase conserved sequence is Asp-Ala-Cys-Glu-Gly-Asp-Ser-Gly-Gly-Pro-Phe-Val.

### Claim 6 (depends on 4)

The composition of claim 4 wherein the serine esterase conserved sequence comprises AspAla-Cys-Glu-Gly-Asp-Ser-Gly-Gly-Pro-Phe-Val.