Peptides and pharmaceutical compositions thereof for treatment of disorders or diseases associated with abnormal protein folding into amyloid or amyloid-like deposits

Abstract

Novel peptides capable of interacting with a hydrophobic β-sheet forming cluster of amino acid residues on a protein or peptide for amyloid or amyloid-like deposit formation inhibit and structurally block the abnormal folding of proteins and peptides into amyloid or amyloid-like deposits and into pathological β-sheet-rich conformation as precursors thereof. Methods for preventing, treating or detecting disorders or diseases associated with amyloid-like fibril deposits, such as Alzheimer's disease and prion-related encephalopathies, are also provided.

What is claimed is:  
     
         1 . An isolated inhibitory peptide, comprising a portion of at least three amino acid residues, which portion is hydrophobic and has one or more β-sheet blocking amino acid residues therein, said inhibitory peptide consisting of a sequence predicted not to adopt a β-sheet structure as calculated by the Chou and Fasman secondary structure prediction algorithm, with the proviso that said inhibitory peptide is not any of the following peptides: SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO:62, SEQ ID NO: 63, SEQ ID NO: 64, and SEQ ID NO: 65, wherein said inhibitory peptide associates with a hydrophobic β-sheet cluster on a protein or peptide involved in the abnormal folding into a β-sheet structure and in the formation of amyloid or amyloid-like deposits, or pathological β-sheet precursors thereof, to structurally block the abnormal folding of said protein or peptide.  
     
     
         2 . The isolated inhibitory peptide in accordance with  claim 1 , wherein said hydrophobic portion of said inhibitory peptide comprises at least three residues identical to said hydrophobic β-sheet forming cluster of said protein or peptide, wherein said hydrophobic portion is interrupted by one or more β-sheet blocking amino acid residues to prevent having more than three contiguous amino acids within said hydrophobic portion to be identical to the corresponding amino acids in said hydrophobic β-sheet forming cluster of said protein or peptide, and wherein any non-hydrophobic residues in said cluster are optionally deleted in said inhibitory peptide.  
     
     
         3 . The isolated inhibitory peptide in accordance with  claim 2 , wherein any non-hydrophobic residues in said cluster are deleted in said inhibitory peptide.  
     
     
         4 . The isolated inhibitory peptide in accordance with  claim 1 , wherein said one or more β-sheet blocking amino acid residues is selected from the group consisting of Pro, Gly, Asn, and His.  
     
     
         5 . The isolated inhibitory peptide in accordance with  claim 1 , wherein said one or more β-sheet blocking amino acid residues are Pro.  
     
     
         6 . The isolated inhibitory peptide in accordance with  claim 1 , wherein one or more charged residues are present on one or both ends of said inhibitory peptide to improve the solubility of said inhibitory peptide.  
     
     
         7 . The isolated inhibitory peptide in accordance with  claim 1 , wherein at least some amino acid residues of said sequence are D-amino acid residues.  
     
     
         8 . A composition, comprising the isolated inhibitory peptide of  claim 1  and a pharmaceutically acceptable carrier.