Peptides antibodies directed thereagainst and methods using same for diagnosing and treating amyloid-associated diseases

Abstract

Peptides having at least 2 amino acids and no more than 15 amino acids are provided. The peptides comprise amino acid sequence X-Y or Y-X, wherein X is an aromatic amino acid and Y is any amino acid other than glycine. Also provided are pharmaceutical compositions and kits including such peptides as well as methods using same for diagnosing and treating amyloid associated diseases.

1 . A peptide comprising amino acid sequence X-Y or Y-X, wherein X is an aromatic amino acid and Y is any amino acid other than glycine, the peptide being at least 2 and no more than 15 amino acids in length.  
     
     
         2 - 11 . (canceled)  
     
     
         12 . The peptide of  claim 1 , selected from the group consisting of SEQ ID NOs. 4, 12-19, 27-45, 112-123, 125, 127, 128-149 and 150.  
     
     
         13 - 39 . (canceled)  
     
     
         40 . A method of treating or preventing an amyloid-associated disease in an individual, the method comprising providing to the individual a therapeutically effective amount of a peptide including the amino acid sequence X-Y or Y-X, wherein X is an aromatic amino acid and Y is any amino acid other than glycine, said peptide being at least 2 and no more than 15 amino acids in length.  
     
     
         41 - 73 . (canceled)  
     
     
         72 . A pharmaceutical composition for treating or preventing an amyloid-associated disease comprising as an active ingredient a peptide including the amino acid sequence X-Y or Y-X, wherein X is an aromatic amino acid and Y is any amino acid other than glycine, said peptide being at least 2 and no more than 15 amino acids in length and a pharmaceutically acceptable carrier or diluent.  
     
     
         73 . The pharmaceutical composition of  claim 72 , wherein Y is a polar uncharged amino acid selected from the group consisting of serine, threonine, asparagine, glutamine and natural derivatives thereof.  
     
     
         74 . The pharmaceutical composition of  claim 72 , wherein Y is a β-sheet breaker amino acid.  
     
     
         75 . The pharmaceutical composition of  claim 74 , wherein said β-sheet breaker amino acid is a naturally occurring amino acid.  
     
     
         76 . The pharmaceutical composition of  claim 75 , wherein said naturally occurring amino acid is selected from the group consisting of proline, aspartic acid, glutamic acid, glycine, lysine and serine.  
     
     
         77 . The pharmaceutical composition of  claim 74 , wherein said β-sheet breaker amino acid is a synthetic amino acid.  
     
     
         78 . The pharmaceutical composition of  claim 77 , wherein said synthetic amino acid is a Cα-methylated amino acid.  
     
     
         79 . The pharmaceutical composition of  claim 78 , wherein said Cα-methylated amino acid is α-aminoisobutyric acid.  
     
     
         80 . (canceled)  
     
     
         81 . The pharmaceutical composition of  claim 72 , wherein said peptide is selected from the group consisting of SEQ ID NOs. 4, 12-19, 27-45, 112-123, 125 and 127.  
     
     
         82 . The pharmaceutical composition of  claim 72 , wherein said peptide is at least 4 amino acids in length and includes at least two serine residues at a C-terminus thereof.  
     
     
         83 . The pharmaceutical composition of  claim 72 , wherein said peptide is at least 3 amino acids in length and whereas at least one of said amino acids of said peptide other than X-Y is a polar uncharged amino acid selected from the group consisting of serine, threonine, asparagine, glutamine and natural derivatives thereof.  
     
     
         84 . The pharmaceutical composition of  claim 72 , wherein said peptide is at least 3 amino acids in length and whereas at least one of said amino acids of said peptide other than X-Y is a is a β-sheet breaker amino acid.  
     
     
         85 . The pharmaceutical composition of  claim 84 , wherein said β-sheet breaker amino acid is a naturally occurring amino acid.  
     
     
         86 . The pharmaceutical composition of  claim 85 , wherein said naturally occurring amino acid is selected from the group consisting of proline, aspartic acid, glutamic acid, glycine, lysine and serine.  
     
     
         87 . The pharmaceutical composition of  claim 84 , wherein said β-sheet breaker amino acid is a synthetic amino acid.  
     
     
         88 . The pharmaceutical composition of  claim 87 , wherein said synthetic amino acid is a Cα-methylated amino acid.  
     
     
         89 . The pharmaceutical composition of  claim 88 , wherein said Cα-methylated amino acid is α-aminoisobutyric acid.  
     
     
         90 . The pharmaceutical composition of  claim 84 , wherein said α-sheet breaker amino acid is located downstream to said X-Y in said peptide.  
     
     
         91 . The pharmaceutical composition of  claim 84 , wherein said β-sheet breaker amino acid is located upstream to said X-Y in said peptide.  
     
     
         92 . The pharmaceutical composition of  claim 72 , wherein said peptide is at least 3 amino acids in length and whereas at least one of said amino acids of said peptide is a positively charged amino acid and at least one of said amino acids of said peptide is a negatively charged amino acid.  
     
     
         93 . The pharmaceutical composition of  claim 92 , wherein said positively charged amino acid is selected from the group consisting of lysine, arginine, and natural and synthetic derivatives thereof.  
     
     
         94 . The pharmaceutical composition of  claim 92 , wherein said negatively charged amino acid is selected from the group consisting of aspartic acid, glutamic acid and natural and synthetic derivatives thereof.  
     
     
         95 . The pharmaceutical composition of  claim 72 , wherein at least one amino acid of said at least 2 and no more than 15 amino acids of the peptide is a D stereoisomer.  
     
     
         96 . The pharmaceutical composition of  claim 72 , wherein at least one amino acid of said at least 2 and no more than 15 amino acids of the peptide is an L stereoisomer.  
     
     
         97 . The pharmaceutical composition of  claim 72 , wherein the peptide is two amino acids in length and Y is a β-sheet breaker amino acid.  
     
     
         98 . The pharmaceutical composition of  claim 97 , wherein the peptide is as set forth in SEQ ID NO: 145.  
     
     
         99 . The pharmaceutical composition of  claim 72 , wherein the peptide is 3 amino acids in length, whereas Y is an aromatic amino acid and an amino acid residue attached to said amino acid sequence X-Y or Y-X is a β-sheet breaker amino acid.  
     
     
         100 . The pharmaceutical composition of  claim 99 , wherein said β-sheet breaker amino acid is at a C-terminus of the peptide.  
     
     
         101 . The pharmaceutical composition of  claim 72 , wherein the peptide is at least 3 amino acids in length and includes a thiolated amino acid at an N-terminus thereof.  
     
     
         102 . A nucleic acid construct comprising a polynucleotide segment encoding the peptide of  claim 1 .  
     
     
         103 - 117 . (canceled)  
     
     
         118 . An antibody or an antibody fragment comprising an antigen recognition region capable of binding the peptide of  claim 1 .  
     
     
         119 - 140 . (canceled)  
     
     
         141 . A pharmaceutical composition for treating or preventing an amyloid-associated disease comprising as an active ingredient an antibody or an antibody fragment having an antigen recognition region capable of binding the peptide of  claim 1  and a pharamaeutical acceptable carrier or diluent.  
     
     
         142 - 147 . (canceled)  
     
     
         148 . A method of treating or preventing an amyloid-associated disease in an individual, the method comprising providing to the individual therapeutically effective amount of an antibody or an antibody fragment having an antigen recognition region capable of binding the peptide of  claim 1 , thereby treating or preventing the amyloid-associated disease in the individual.  
     
     
         149 - 154 . (canceled)  
     
     
         155 . A peptide having the general Formula:  
       
         
           
           
               
               
           
         
         wherein:  
         C* is a chiral carbon having a D configuration.  
         R 1  and R 2  are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carboxy, C-thiocarb;  
         R 3  is selected from the group consisting of hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, halo and amine; and  
         R4 is alkyl.  
       
     
     
         156 . The peptide of  claim 155 , wherein R 4  is methyl.  
     
     
         157 . The peptide of  claim 155 , wherein R 1  and R 2  are each hydrogen and R 3  is hydroxy.  
     
     
         158 . The peptide of  claim 155  is a cyclic peptide.  
     
     
         159 . A method of treating or preventing an amyloid-associated disease in an individual, the method comprising providing to the individual a therapeutically effective amount of the peptide  
     
     
         160 - 162 . (canceled)