Synthetic inhibitors of hepatitis C virus NS3 protease

• US 5,990,276 A
• Filed: 05/09/1997
• Issued: 11/23/1999
• Est. Priority Date: 05/10/1996
• Status: Expired due to Fees

• Current Assignee: Schering Corporation (Merck & Co., Inc.)
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Mui, Philip W., Zhang, Rumin, Weber, Patricia C.
• Primary Examiner(s): MOSHER, MARY
• Application Number:
  US08/853,623
• Time in Patent Office: 928 Days
• Field of Search: 435/320.1, 435/69.7, 435/183, 435/212, 435/219, 435/236, 536/23.2, 536/23.4, 530/326, 530/327, 530/332, 530/402, 514/2, 514/13-15, 930/10, 930/21, 930/30, 930/220
• US Class Current: 530/326
• 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: C07K 14/005 from viruses
• CPC Class Codes: C12N 2770/24222 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12N 9/506 derived from RNA viruses

Abstract

An inhibitor of the HCV NS3 protease. The inhibitor is a subsequence of a substrate of the NS3 protease or a subsequence of the NS4A cofactor. Another inhibitor of the present invention contains a subsequence of a substrate linked to a subsequences of the NS4A cofactor. In another embodiment the inhibitor is a bivalent inhibitor comprised of a subsequence, a mutated subsequence or a mutated full-length of a substrate of the NS3 protease linked to a subsequence, a mutated subsequence or a mutated full-length suquence of the HCV NS4A cofactor.

Claims

1. A bivalent inhibitor of a hepatitis C NS3 protease comprised of a first peptide, a second peptide, and a linker, wherein

said first peptide comprises a subsequence, a mutated subsequence or a mutated full-length sequence of a substrate of the hepatitis C NS3 protease which is not cleaved by the protease;

said second peptide comprises a subsequence of a hepatitis C NS4A polypeptide selected from the group consisting of SEQ ID NO;

9, SEQ ID NO;

10, SEQ ID NO;

11, SEQ ID NO;

12, SEQ ID NO;

13, SEQ ID NO;

14 and SEQ ID NO;

15; and

said linker comprises a chemical entity capable of forming a bond with said first peptide and said second peptide and is equivalent in length to a carbon chain having about 7-14 carbon atoms.

2. The bivalent inhibitor of claim 1 selected from the group consisting of SEQ ID NO:

1, SEQ ID NO;

2, SEQ ID NO;

3, SEQ ID NO;

4, SEQ ID NO;

5, SEQ ID NO;

6, SEQ ID NO;

7, and SEQ ID NO;

8.

3. The bivalent inhibitor of claim 1, conjugated to a carrier protein.

4. The bivalent inhibitor of claim 3, wherein the carrier protein is selected from the group consisting of ovalbumin and serum albumin.

5. A monovalent inhibitor of a hepatitis C NS3 protease selected from the group consisting of SEQ ID NO:

9, SEQ ID NO;

10, SEQ ID NO;

11, SEQ ID NO;

12, SEQ ID NO;

13, SEQ ID NO;

14 and SEQ ID NO;

15.

6. The monovalent inhibitor of claim 5, conjugated to a carrier protein.

7. The monovalent inhibitor of claim 6, wherein the carrier protein is selected from the group consisting of ovalbumin and serum albumin.