Interleukin 1beta protease and interleukin 1beta protease inhibitors

Abstract

There is disclosed an isolated polypeptide and derivatives thereof having protease biological activity for human precursor IL-1β and for a substrate comprising: R 1 -Asp-R 2 -R 3 wherein R 1 and R 3 are independently any D or L isomer amino acid, R 2 is Ala or Gly, and wherein the specific protease cleavage site is between Asp and R 2 . Inhibitor compounds, compositions and methods for inhibiting Interleukin 1β protease activity are also disclosed. The inhibitor compounds comprise an amino acid sequence of from 1 to about 5 amino acids having an N-terminal blocking group and a C-terminal Asp residue connected to an electronegative leaving group, wherein the amino acid sequence corresponds to the sequence Ala-Tyr-Val-His-Asp.

1 . An isolated polypeptide having protease activity for a specific protease cleavage site, wherein the protease activity is specific for a substrate peptide having an amino acid sequence comprising:  
         R 1 -Asp-R 2 -R 3    wherein R 1  and R 3  are independently any D or L isomer amino acid, R 2  is Ala or Gly, and wherein the specific protease cleavage site is between Asp and R 2 .    
     
     
         2 . The isolated polypeptide of  claim 1  wherein the substrate peptide is at least eight amino acids in length.  
     
     
         3 - 13 . (canceled)  
     
     
         14 . A method for improving wound healing at a wound site comprising administering a pharmaceutical composition to the wound site comprising the isolated polypeptide of  claim 1  in a suitable pharmaceutical carrier.  
     
     
         15 . A method for treating arthritis comprising administering a pharmaceutical composition comprising the isolated polypeptide of  claim 1  in a suitable pharmaceutical carrier.  
     
     
         16 . A method for treating an autoimmune disease in a susceptible individual comprising administering a pharmaceutical composition comprising the isolated polypeptide of  claim 1  in a suitable pharmaceutical carrier.  
     
     
         17 . The method of  claim 16  wherein the autoimmunedisease is selected from the group consisting of Insulin-dependent diabetes melitus, Graves' disease, Hashimotos disease and a lupus disease.  
     
     
         18 . A method for reducing the detrimental side effects of radiation treatment comprising administering a pharmaceutical composition comprising the isolated polypeptide of  claim 1  in a suitable pharmaceutical carrier.  
     
     
         19 - 49 . (canceled)