Methods and compositions for derepression of IAP-inhibited caspase

Abstract

The invention provides isolated agents having a core peptide selected from the group consisting of Core peptides 5 through 39 and 42 through 55, wherein the agent derepresses an IAP-inhibited caspase. Also provided is an isolated agent having a core structure selected from any of the structures shown in FIGS. 5, 9, 10, 14 B, and 21 - 24 wherein said agent derepresses an IAP-inhibited caspase. The invention further provides a method of derepressing an IAP-inhibited caspase. The method consists of contacting an IAP-inhibited caspase with an effective amount of an agent to derepress an IAP-inhibited caspase, the agent having a core motif selected from the group consisting of a core peptide having a sequence set forth in any of Core peptides 4 through 39 and 42 through 55, and a core structure selected from the group consisting of TPI759, TPI882, TPI914 or TPI927. The methods of the invention also can be used for promoting apoptosis in a cell and for reducing the severity of a pathology characterized by reduced levels of apoptosis. Methods for identifying agents that derepress an IAP-inhibited caspase are also provided.

1 - 21 . (canceled)  
     
     
         22 . A method of identifying an agent that derepresses an IAP-inhibited caspase, comprising: 
 (a) detecting a labeled derepressor of an    IAP-inhibited caspase bound to an IAP or caspase, said labeled derepressor of an IAP-inhibited caspase comprising a core motif selected from a core sequence set forth in any of Core peptides 4 through 39 and 42 through 55, or a core structure selected from the group consisting of TP1759, TP1882, TPI914 and TP1927;    (b) contacting the bound IAP or caspase with a    candidate agent, said candidate agent suspected of being able to derepress an IAP-inhibited caspase; and    (c) detecting dissociation of said labeled    derepressor of an IAP-inhibited caspase from said LAP or caspase, whereby said candidate agent is identified as an agent that derepresses an IAP-inhibited caspase.    
     
     
         23 . The method of  claim 22 , wherein the IAP is selected from the group consisting of XIAP, c-IAP-1, c-IAP-2, and survivin.  
     
     
         24 . The method of  claim 22 , wherein said IAP-inhibited caspase is selected from the group consisting of caspase-3, caspase-7 and caspase-9.  
     
     
         25 . The method of  claim 22 , wherein said contacting is performed in vitro.  
     
     
         26 . The method of  claim 22 , wherein said contacting occurs in a cell.