Stabilized alpha helical peptides and uses thereof

Abstract

Novel polypeptides and methods of making and using the same are described herein. The polypeptides include cross-linking (“hydrocarbon stapling”) moieties to provide a tether between two amino acid moieties, which constrains the secondary structure of the polypeptide. The polypeptides described herein can be used to treat diseases characterized by excessive or inadequate cellular death.

1 - 37 . (canceled) 
     
     
         38 . An α-helix containing polypeptide of Formula (III): 
       
         
           
           
               
               
           
         
         wherein; 
         each R 1  and R 2  are independently H, C 1 -C 20  alkyl, C 2 -C 20  alkenyl, C 2 -C 20  alkynyl, arylalkyl, 
         cycloalkylalkyl, heteroarylalkyl, or heterocyclylalkyl; 
         each n is independently an integer from 1-15; 
         x is 2, 3 or 6; 
         each y is independently an integer from 0-100; 
         z is an integer from 1-10; 
         each Xaa is independently an amino acid and is the same amino acid as in another α-helix containing pro-apoptotic or anti-apoptotic polypeptide; and 
         the α-helix containing polypeptide of Formula (III) is pro-apoptotic or anti-apoptotic. 
       
     
     
         39 . The α-helix containing polypeptide of  claim 38 , wherein —(CH 2 ) n   (CH 2 ) n — is C 8  alkyl or C 11  alkyl. 
     
     
         40 . The α-helix containing polypeptide of  claim 38 , wherein —(CH 2 ) n   (CH 2 ) n — is C 8  alkenyl or C 11  alkenyl. 
     
     
         41 . The α-helix containing polypeptide of  claim 38 , wherein R 1  and R 2  are independently H or C 1-6  alkyl. 
     
     
         42 . The α-helix containing polypeptide of  claim 38 , wherein the polypeptide comprises a BH3 domain. 
     
     
         43 . The α-helix containing polypeptide of  claim 38 , wherein x is 3 or 6, and z is 1. 
     
     
         44 . The α-helix containing polypeptide of  claim 38 , wherein each y is independently an integer between 1 and 15. 
     
     
         45 . The α-helix containing polypeptide of  claim 38 , wherein R 1  and R 2  are independently C 1 -C 3  alkyl. 
     
     
         46 . The α-helix containing polypeptide of  claim 45 , wherein at least one of R 1  and R 2  is methyl. 
     
     
         47 . The α-helix containing polypeptide of  claim 38 , wherein x is 3 or 6, and R 1  and R 2  are methyl. 
     
     
         48 . The α-helix containing polypeptide of  claim 38 , wherein the polypeptide comprises an amino acid sequence which is at least about 60% identical to the amino acid sequence of SEQ ID NO:1, or an amino acid sequence which is at least about 80% identical to the amino acid sequence of SEQ ID NO:2. 
     
     
         49 . The α-helix containing polypeptide of  claim 48 , wherein at least one of R 1  and R 2  is C 1-6  alkyl. 
     
     
         50 . The α-helix containing polypeptide of  claim 38 , further comprising a fluorescent moiety, a radioisotope, an affinity label, a targeting moiety or a biotin moiety. 
     
     
         51 . The α-helix containing polypeptide of  claim 38 , wherein the polypeptide is selected from the group consisting of the polypeptides depicted in  FIG. 5 .