Discordant helix stabilization for prevention of amyloid formation

Abstract

The invention is based on the discovery that the presence of a discordant helix in a protein or peptide is predictive of that protein or peptide's ability to form amyloid. The invention includes methods for detecting discordant helices and methods of screening for compounds that stabilize the α-helix of a discordant helix-containing polypeptide. Compounds discovered using these methods are useful for treating or preventing disorders in which amyloid is produced. Such disorders include Alzheimer's disease and prion-associated disorders.

1 - 4 . (Canceled).  
     
     
         5 . A method of identifying whether a protein is susceptible to forming amyloid, the method comprising analyzing the amino acid sequence of the protein to determine whether the protein contains a predicted discordant helix, wherein the presence of predicted discordant helix is an indication that the protein is susceptible to forming amyloid.  
     
     
         6 . The method of  claim 5 , wherein the discordant helix is at least six amino acids in length.  
     
     
         7 . A method of decreasing the rate of formation of β-strand structures between at least two discordant helix-containing polypeptides, the method comprising contacting the discordant helix-containing polypeptides with a compound that stabilizes an α-helical form of the discordant helix.  
     
     
         8 . A method of treating an individual having or at risk for an amyloidosis, the method comprising administering to the individual a therapeutically effective amount of a compound that stabilizes an α-helical form of a discordant helix-containing polypeptide that forms amyloid.  
     
     
         9 . The method of  claim 8 , wherein the amyloidosis is selected from the group consisting of prion diseases and Alzheimer's disease.