ATP-dependent protease and use of inhibitors for same in the treatment of cachexia and muscle wasting

• US 5,340,736 A
• Filed: 05/13/1991
• Issued: 08/23/1994
• Est. Priority Date: 05/13/1991
• Status: Expired due to Term

• Current Assignee: Harvard University
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Goldberg, Alfred L.
• Primary Examiner(s): Patterson, Jr., Charles L.
• Application Number:
  US07/699,184
• Time in Patent Office: 1,198 Days
• Field of Search: 435/219, 435/226
• US Class Current: 435/226
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: C07K 14/8139 Cysteine protease (E.C. 3.4.22) inhibitors, e.g. cystatin
• CPC Class Codes: C12N 9/6421 from mammals
• CPC Class Codes: C12Q 1/37 involving peptidase or proteinase
• CPC Class Codes: G01N 2333/96466 Cysteine endopeptidases (3.4.22)
• CPC Class Codes: G01N 2500/20 cell-free systems

Abstract

The ATP-ubiquitin-dependent process has been shown to be responsible for the excessive protein degradation which occurs in conditions or disease states in which there is severe loss of body mass and negative nitrogen balance has been identified and key constituents in the process identified. A method of inhibiting the accelerated or enhanced proteolysis, a method of identifying inhibitors of the process, multipain and the proteasome inhibitor are the subject of the claimed invention.

Claims

1. Isolated component of the Ubiquitin-Conjugate-Degrading-Enzyme, said isolated component selected from the group consisting of:

(a) multipain of approximately 500 kDa, which has a proteolytic activity that preferentially cleaves ubiquitinated proteins in an ATP-dependent manner; and

(b) multipain-proteasome complex of approximately 1500 kDa, comprising the multipain of (a) and the proteasome, said complex which has a proteolytic activity that cleaves ubiquitinated and non-ubiquitinated proteins in an ATP-dependent manner.

2. The isolated component of claim 1 which is isolated from muscle.