Structure-based peptide inhibitors of alpha-synuclein aggregation

Abstract

This invention relates to inhibitory peptides which bind to α-synuclein molecules and inhibit α-synuclein amyloidogenic aggregation, α-synuclein cytotoxicity, and spread of α-synuclein. Methods of making and using the inhibitory peptides (e.g. to treat subjects having conditions or diseases that are mediated by α-synuclein, such as Parkinson's disease, dementia with Lewy bodies, or MSA) are described.

1 . A composition of matter comprising at least one inhibitory peptide that inhibits α-synuclein (SEQ ID NO: 1) aggregation by binding to residues 68-78 of α-synuclein; wherein:
 (a) the inhibitory peptide comprises the sequence: 
 GAVVWGVTAVKK (SEQ ID NO: 3); or 
 RAVVTGVTAVAE (SEQ ID NO: 4); and 
 
       at least one of the amino acids in the inhibitory peptide comprises a non-naturally occurring amino acid; and/or
 the inhibitory peptide is coupled to a heterologous peptide tag. 
 
     
     
         2 . The composition of  claim 1 , wherein the inhibitory peptide comprises the sequence: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 5) 
                 
                     
                   GAVVWGVTAVKKKKK; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 6) 
                 
                     
                   GAVVWGVTAVKKGRKKRRQRRRPQ; 
                 
                     
                   or 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 7) 
                 
                     
                   YGRKKRRQRRRAVVTGVTAVAE. 
                 
             
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         3 . The composition of  claim 1 , wherein the non-naturally occurring amino acid comprises at least one of:
 a D-amino acid; or   an amino acid comprising a N-methyl group moiety.   
     
     
         4 . The composition of  claim 1 , wherein the heterologous peptide tag comprises:
 an amino acid sequence that increases peptide solubility;   an amino acid sequence that facilitates monitoring of the peptide; and/or   an amino acid sequence that facilitates peptide entry into a mammalian cell.   
     
     
         5 . The composition of  claim 4 , wherein the heterologous peptide tag comprises:
 a plurality of arginine residues;   a plurality of lysine amino acids; and/or   an amino acid sequence TAT.   
     
     
         6 . The composition of  claim 1 , wherein the inhibitory peptide is from 6 to 30 amino acids in length. 
     
     
         7 . The composition of  claim 1 , wherein the composition comprises a plurality of inhibitory peptides. 
     
     
         8 . A pharmaceutical composition comprising a peptide of  claim 1 , and a pharmaceutically acceptable carrier including a peptide stabilizing excipient. 
     
     
         9 . A complex comprising α-synuclein and a peptide composition of  claim 1 . 
     
     
         10 - 20 . (canceled)