Stereoselective antifibrillogenic peptides and peptidomimetics thereof

Abstract

The present invention relates to antifibrillogenic agents for inhibiting amyloidosis and/or for cytoprotection for the treatment of amyloidosis disorders. These agents include peptides, isomers thereof and peptidomimetic compounds thereof. These agents comprise a peptide having a sequence identified from the glycosaminoglycan (GAG) binding region and the prot-prot interaction region of the amyloid protein. The peptide has at least one [D] amino acid isomer substitution. The invention also relates to the peptide bound to a label for in vivo imaging of amyloid deposits.

1 . A peptide for the prevention or treatment of an amyloidosis disorder in a human, said peptide comprising a sequence of [D]-amino acids selected from the group consisting of: (i) Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4  and (ii) retro-isomer sequences of Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 , wherein: Xaa 1  is Lys; 
 Xaa 2  is Ile, Lys-Leu, Phe, Ala, Val, or Leu;    Xaa 3  is Val; and    Xaa 4  is Phe-Phe-Ala, Phe-Phe-Ala-NH 2 , Phe-Phe-Ala-Gln, or Phe-Phe-Ala-Gln-NH 2 ;    with the proviso that Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4  is not Lys-Leu-Val-Phe-Phe-Ala.    
     
     
         2 . The peptide of  claim 1 , wherein said sequence of [D]-amino acids is selected from the group consisting of:  
       
         
           
                 
                 
                 
               
                     
                 
                   Lys-Ile-Val-Phe-Phe-Ala; 
                   (SEQ ID NO:1) 
                     
                 
                     
                 
                   Lys-Lys-Leu-Val-Phe-Phe-Ala; 
                   (SEQ ID NO:2) 
                 
                     
                 
                   Lys-Phe-Val-Phe-Phe-Ala; 
                   (SEQ ID NO:4) 
                 
                     
                 
                   Lys-Ala-Val-Phe-Phe-Ala; 
                   (SEQ ID NO:7) 
                 
                     
                 
                   Lys-Val-Val-Phe-Phe-Ala; 
                   (SEQ ID NO:9) 
                 
                     
                 
                   Lys-Ile-Val-Phe-Phe-Ala-NH 2 ; 
                   (SEQ ID NO:10) 
                 
                     
                 
                   Lys-Phe-Val-Phe-Phe-Ala-NH 2 ; 
                   (SEQ ID NO:12) 
                 
                     
                 
                   Lys-Ala-Val-Phe-Phe-Ala-NH 2 ; 
                   (SEQ ID NO:15) 
                 
                     
                 
                   Lys-Val-Val-Phe-Phe-Ala-NH 2 ; 
                   (SEQ ID NO:17) 
                 
                     
                 
                   Lys-Leu-Val-Phe-Phe-Ala-Gln; 
                   (SEQ ID NO:18) 
                 
                     
                 
                   Lys-Leu-Val-Phe-Phe-Ala-Gln-NH 2 ; 
                   (SEQ ID NO:19) 
                 
                     
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         and retro-isomer sequences thereof.  
       
     
     
         3 . The peptide of  claim 1 , wherein said peptide is associated to a pharmaceutically acceptable carrier.  
     
     
         4 . The peptide of  claim 1 , wherein said amyloidosis disorder is Alzheimer's disease.  
     
     
         5 . The peptide of  claim 1 , wherein said peptide is for preventing the development of Alzheimer's disease in a human.  
     
     
         6 . The peptide of  claim 1 , wherein said peptide is for arresting the development of Alzheimer's disease in a human.  
     
     
         7 . A peptide comprising a sequence of [D]-amino acids, wherein said sequence [D]-amino acids is Lys-Lys-Leu-Val-Phe-Phe-Ala (SEQ ID NO:2) or the retro-isomer sequence thereof.  
     
     
         8 . A medicament for the prevention or treatment of an amyloidosis disorder in a human, said medicament comprising a peptide as defined in  claim 1 .  
     
     
         9 . The medicament of  claim 8 , wherein said medicament is for preventing or for arresting the development of Alzheimer's disease in a human.  
     
     
         10 . A method for blocking or preventing an amyloidosis disorder in a patient, said method comprising administering to said patient a peptide comprising a sequence of [D]-amino acids selected from the group consisting of: (i) Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4  and (ii) retro-isomer sequences of Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 ,  
       wherein: Xaa 1  is Lys; 
 Xaa 2  is Ile, Lys-Leu, Phe, Ala, Val, or Leu;  
 Xaa 3  is Val; and  
 Xaa 4  is Phe-Phe-Ala, Phe-Phe-Ala-NH 2 , Phe-Phe-Ala-Gln, or Phe-Phe-Ala-Gln-NH 2 ;  
 with the proviso that Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4  is not Lys-Leu-Val-Phe-Phe-Ala.  
 
     
     
         11 . The method of  claim 10 , wherein said sequence of [D]-amino acids is selected from the group consisting of:  
       
         
           
                 
                 
                 
               
                     
                 
                   Lys-Ile-Val-Phe-Phe-Ala; 
                   (SEQ ID NO:1) 
                     
                 
                     
                 
                   Lys-Lys-Leu-Val-Phe-Phe-Ala; 
                   (SEQ ID NO:2) 
                 
                     
                 
                   Lys-Phe-Val-Phe-Phe-Ala; 
                   (SEQ ID NO:4) 
                 
                     
                 
                   Lys-Ala-Val-Phe-Phe-Ala; 
                   (SEQ ID NO:7) 
                 
                     
                 
                   Lys-Val-Val-Phe-Phe-Ala; 
                   (SEQ ID NO:9) 
                 
                     
                 
                   Lys-Ile-Val-Phe-Phe-Ala-NH 2 ; 
                   (SEQ ID NO:10) 
                 
                     
                 
                   Lys-Phe-Val-Phe-Phe-Ala-NH 2 ; 
                   (SEQ ID NO:12) 
                 
                     
                 
                   Lys-Ala-Val-Phe-Phe-Ala-NH 2 ; 
                   (SEQ ID NO:15) 
                 
                     
                 
                   Lys-Val-Val-Phe-Phe-Ala-NH 2 ; 
                   (SEQ ID NO:17) 
                 
                     
                 
                   Lys-Leu-Val-Phe-Phe-Ala-Gln; 
                   (SEQ ID NO:18) 
                 
                     
                 
                   Lys-Leu-Val-Phe-Phe-Ala-Gln-NH 2 ; 
                   (SEQ ID NO:19) 
                 
                     
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         and retro-isomer sequences thereof.  
       
     
     
         12 . The method of  claim 10 , wherein said peptide is associated to a pharmaceutically acceptable carrier.  
     
     
         13 . The method of  claim 10 , wherein said patient is in need of a treatment against an amyloidosis disorder.  
     
     
         14 . The method of  claim 10 , wherein said amyloidosis disorder is Alzheimer's disease.  
     
     
         15 . The method of  claim 10 , wherein said method is for preventing the development of Alzheimer's disease.  
     
     
         16 . The method of  claim 10 , wherein said method is for arresting the development of Alzheimer's disease.  
     
     
         17 . A method for preventing or for arresting the development of Alzheimer's disease in a human, said method comprising administering to a patient a peptide comprising a sequence of [D]-amino acids, wherein said sequence is Lys-Lys-Leu-Val-Phe-Phe-Ala (SEQ ID NO:2) or the retro-isomer thereof.