Beta-sheet breaker peptide analogs that inhibit beta-pleated sheet formation in amyloid beta-peptide

Abstract

The present invention provides peptide analogs and peptide mimetics that inhibit pleated sheet formation in amyloid β-peptide, pharmaceutical compositions thereof and their therapeutic use. The inhibitory peptides possess activity as inhibitors in the formation of amyloid-like deposits and are useful in the treatment of Alzheimer's Disease.

1 . A compound capable of inhibiting conformational changes in a prion PrP protein associated with amyloidosis, said compound comprising: 
 a β-sheet breaker peptide analog produced by chemical modification of a 13-residue prion inhibitor peptide iPrP 13 (SEQ ID NO:2), and able to inhibit said conformational changes in prion PrP protein associated with amyloidosis.    
     
     
         2 . The compound of  claim 1 , wherein alteration of the N- and C-terminal ends of said iPrP13 is achieved by a process selected from the group consisting of acetylation, amidation, desamination, alcoholization, and combinations thereof.  
     
     
         3 . A compound comprising: a β-sheet breaker peptide analog produced by chemically modifying iPrP 13 (SEQ ID NO:2), capable of inhibiting a conformational change in a prion PrP protein associated with amyloidosis, wherein said chemical modification is achieved by a process selected from the group consisting of: 
 alteration of the N- and C-terminal ends of said prion inhibitor peptide iPrP13;    replacing at least one residue of said prion inhibitor peptide iPrP 13 with α-aminoisobuiric acid (Aib);    methylation of the α carbon of at least one residue of said prion inhibitor peptide iPrP13 with a D-enantiomeric residue;    forming head-to-tail cyclization of said prion inhibitor peptide iPrP13;    replacing amide bonds in said prion inhibitor peptide iPrP13 with an amide bond surrogate; and combinations thereof.    
     
     
         4 . The compound of  claim 3 , wherein alteration of the N- and C-terminal ends of said iPrP13 is achieved by a process selected from the group consisting of acetylation, amidation, desamination, alcoholization, and combinations thereof.  
     
     
         5 . The compound of  claim 4 , wherein said β-sheet breaker peptide analog is selected from the group consisting of: ac-Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro Val-am, des-Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro Val-am, ac-Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro Val-alc, and des-Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro Val-alc.  
     
     
         6 . The compound of  claim 4 , wherein said 1-sheet breaker peptide analog is selected from the group consisting of: 
 Asp Ala Alb Ala Ala Aib Ala Gly Aib Ala Val Aib Val (SEQ ID NO: 4);    Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala (Me) Val Pro Val;    Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro (Me) Val;    Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala (Me) Val Pro (Me) Val;    asp ala pro ala ala pro ala gly pro ala val pro val;    asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro val;    asp Ala Pro ala Ala Pro ala Gly Pro ala Val Pro val;    Aspψ[CH 2 CH 2 ]Ala Proψ[CH 2 CH 2 ]Ala Ala Proψ[CH 2 CH 2 ]Ala Gly Proψ[CH 2 CH 2 ]Ala ValProψ[CH 2 CH 2 ]Val;    Aspψ[CH 2 S]Ala Proψ[CH 2 S]Ala Ala Proψ[CH 2 S]Ala Gly Proψ[CH 2 S]Ala Val Proψ[CH 2 S]Val;    Ac-Asp Ala Proψ[CH 2 CH 2 ]Ala Ala Proψ[CH 2 CH 2 ]Ala Gly Proψ[CH 2 CH 2 ]Ala Val Pro Val-Am.    asp Ala Proψ[CH 2 CH 2 ]Ala Ala Proψ[CH 2 CH 2 ]Ala Gly Proψ[CH 2 CH 2 ]Ala Val Pro val;    Ac-Asp Ala Proψ[CH 2 S]Ala Ala Proψ[CH 2 S]Ala Gly Proψ[CH 2 S]Ala Val Pro Val-Am;    asp Ala Proψ[CH 2 S]Ala Ala Proψ[CH 2 S]Ala Gly Proψ[CH 2 S]Ala Val Pro val;    Ac-Asp Ala Aib Ala Ala Aib Ala Gly Aib Ala Val Pro Val-Am (SEQ ID NO:5);    Ac-Asp Ala Proψ[CH 2 CH 2 ]Ala Ala Proψ[CH 2 CH 2 ]Ala Gly Proψ[CH 2 CH 2 ]Ala Val Pro (Me) Val;    Ac-Asp Ala pro Ala Ala Proψ[CH 2 CH 2 ]Ala Gly pro Ala Val Pro Val-Am;    asp Ala Proψ[CH 2 CH 2 ]Ala Ala Proψ[CH 2 CH 2 ]Ala Gly Proψ[CH 2 CH 2 ]Ala Val Pro (Me) Val;    asp Ala Aib Ala Ala Proψ[CH 2 CH 2 ]Ala Gly pro Ala Val Pro (Me)Val (SEQ ID NO:6);    asp Ala Aib Ala Ala Proψ[CH 2 S]Ala Gly pro Ala Val Pro (Me) Val;    asp Ala Proψ[CH 2 S]Ala Ala Proψ[CH 2 S]Ala Gly Proψ[CH 2 S]Ala Val Pro (Me) Val;    Ac-Asp Ala Aib Ala Ala Proψ[CH 2 CH 2 ]Ala Gly Aib Ala Val Pro (Me) Val (SEQ ID NO:7);                          Asp Ala pro Ala Ala Proψ[CH 2 CH 2 ]Ala Gly pro Ala Val Pro Val    Asp Ala Aib Ala Ala Proψ[CH 2 CH 2 ]Ala Gly Aib Ala (Me) Val Pro Val Pro Val    Ac-Asp Ala Proψ[CH 2 S]Ala ala Proψ[CH 2 S]Ala gly Proψ[CH 2 S]Ala (Me) Val Pro Val-Am;    Ac-Asp Ala Aib ala Ala Proψ[CH 2 CH 2 ]Ala Gly pro Ala Val Pro (Me) Val;    asp Ala Aib Ala Ala Proψ[CH 2 CH 2 ]Ala Gly Aib ala Val Pro Val-Am;    Ac-Asp Ala pro Ala Ala Proψ[CH 2 CH 2 ]Ala gly pro Ala (Me) Val Pro Val-Am;    asp Ala Proψ[CH 2 CH 2 ]Ala Ala Proψ[CH 2 CH 2 ]Ala gly Proψ[CH 2 CH 2 ]Ala val Pro val;    Ac-Asp Ala pro Ala ala Aib Ala gly pro Ala (Me)Val Pro Val-Am (SEQ ID NO:8);    Asp Ala pro Ala Ala Proψ[CH 2 CH 2 ]Ala Gly pro Ala Val Pro Val;    Asp Ala Aib Ala Proψ[CH 2 CH 2 ]Ala Gly Aib Ala (Me) Val Pro Val; and                          
     
     
         7 . A pharmaceutical composition, comprising the β-sheet breaker peptide analog of  claim 3  and a pharmaceutically acceptable excipient or stabilizer.  
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein alteration of the N- and C-terminal ends of said iPrP13 is achieved by a process selected from the group consisting of acetylation, amidation, desamination, alcoholization, and combinations thereof.  
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein said β-sheet breaker peptide analog is selected from the group consisting of: ac-Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro Val-am, des-Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro Val-am, ac-Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro Val-alc, and des-Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro Val-alc.  
     
     
         10 . The pharmaceutical composition of  claim 8 , wherein said β-sheet breaker peptide analog is selected from the group consisting of: 
 Asp Ala Alb Ala Ala Aib Ala Gly Aib Ala Val Aib Val (SEQ ID NO: 4);    Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala (Me) Val Pro Val;    Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro (Me) Val;    Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala (Me) Val Pro (Me) Val;    asp ala pro ala ala pro ala gly pro ala val pro val;    asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro val;    asp Ala Pro ala Ala Pro ala Gly Pro ala Val Pro val;    Aspψ[CH 2 CH 2 ]Ala Proψ[CH 2 CH 2 ]Ala Ala Proψ[CH 2 CH 2 ]Ala Gly Proψ[CH 2 CH 2 ]Ala ValProψ[CH 2 CH 2 ]Val;    Aspψ[CH 2 S]Ala Proψ[CH 2 S]Ala Ala Proψ[CH 2 S]Ala Gly Proψ[CH 2 S]Ala Val Proψ[CH 2 S]Val;    Ac-Asp Ala Proψ[CH 2 CH 2 ]Ala Ala Proψ[CH 2 CH 2 ]Ala Gly Proψ[CH 2 CH 2 ]Ala Val Pro Val-Am.    asp Ala Proψ[CH 2 CH 2 ]Ala Ala Proψ[CH 2 CH 2 ]Ala Gly Proψ[CH 2 CH 2 ]Ala Val Pro val;    Ac-Asp Ala Proψ[CH 2 S]Ala Ala Proψ[CH 2 S]Ala Gly Proψ[CH 2 S]Ala Val Pro Val-Am;    asp Ala Proψ[CH 2 S]Ala Ala Proψ[CH 2 S]Ala Gly Proψ[CH 2 S]Ala Val Pro val;    Ac-Asp Ala Aib Ala Ala Aib Ala Gly Aib Ala Val Pro Val-Am (SEQ ID NO:5);    Ac-Asp Ala Proψ[CH 2 CH 2 ]Ala Ala Proψ[CH 2 CH 2 ]Ala Gly Proψ[CH 2 CH 2 ]Ala Val Pro (Me) Val;    Ac-Asp Ala pro Ala Ala Proψ[CH 2 CH 2 ]Ala Gly pro Ala Val Pro Val-Am;    asp Ala Proψ[CH 2 CH 2 ]Ala Ala Proψ[CH 2 CH 2 ]Ala Gly Proψ[CH 2 CH 2 ]Ala Val Pro (Me) Val;    asp Ala Aib Ala Ala Proψ[CH 2 CH 2 ]Ala Gly pro Ala Val Pro (Me)Val (SEQ ID NO:6);    asp Ala Aib Ala Ala Proψ[CH 2 S]Ala Gly pro Ala Val Pro (Me) Val;    asp Ala Proψ[CH 2 S]Ala Ala Proψ[CH 2 S]Ala Gly Proψ[CH 2 S]Ala Val Pro (Me) Val; (SEQ ID NO:7);                          Ac-Asp Ala Proψ[CH 2 S]Ala ala Proψ[CH 2 S]Ala gly Proψ[CH 2 S]Ala (Me) Val Pro Val-Am;    Ac-Asp Ala Aib ala Ala Proψ[CH 2 CH 2 ]Ala Gly pro Ala Val Pro (Me) Val;    asp Ala Aib Ala Ala Proψ[CH 2 CH 2 ]Ala Gly Aib ala Val Pro Val-Am;    Ac-Asp Ala pro Ala Ala Proψ[CH 2 CH 2 ]Ala gly pro Ala (Me) Val Pro Val-Am;    asp Ala Proψ[CH 2 CH 2 ]Ala Ala Proψ[CH 2 CH 2 ]Ala gly Proψ[CH 2 CH 2 ]Ala val Pro val;    Ac-Asp Ala pro Ala ala Aib Ala gly pro Ala (Me)Val Pro Val-Am (SEQ ID NO:8);    Asp Ala pro Ala Ala Proψ[CH 2 CH 2 ]Ala Gly pro Ala Val Pro Val;    Asp Ala Aib Ala Proψ[CH 2 CH 2 ]Ala Gly Aib Ala (Me) Val Pro Val; and                          
     
     
         11 . A method for reducing formation of amyloid or amyloid like deposits involving conformational changes in a prion PrP protein, or reducing the amount of prion PrP protein that has already formed into amyloid or amyloid-like deposits, said method comprising: 
 bringing into the presence of said prion PrP protein, either prior to or after said conformational changes thereof into amyloid deposits, an effective amount of the compound of  claim 3 .    
     
     
         12 . A method for reducing formation of amyloid or amyloid like deposits involving conformational changes in a prion PrP protein, or reducing the amount of said prion PrP protein which has already formed into amyloid or amyloid-like deposits, said method comprising: 
 bringing into the presence of said prion PrP protein, either prior to or after said conformational changes thereof into amyloid deposits, the pharmaceutical composition of  claim 7  in an amount effective to reduce the formation of amyloid or amyloid like deposits involving conformational changes in a prion PrP protein.    
     
     
         13 . A method of preventing or treating a disorder or disease associated with amyloid or amyloid-like deposits or pathological beta-sheet-rich precursors thereof, the method comprising: 
 administering an effective amount of a compound of  claim 3  to a subject thought to be in need thereof.    
     
     
         14 . The method according to  claim 13 , wherein the subject is thought to be suffering from a disease selected from the group consisting of human prion diseases, prion associated human neurodegenerative diseases and animal prion diseases.  
     
     
         15 . The method according to  claim 14 , wherein the subject is suffering from a disease selected from the group consisting of spongiform encephalopathy, kuru, Creutzfeldt-Jakob Disease, Gerstmann-Strausslet-Scheinker Syndrome, scrapie, transmissible mink encephalopathy, and chronic wasting-disease.  
     
     
         16 . The method according to  claim 13 , wherein the disease is scrapie.  
     
     
         17 . The method according to  claim 13 , wherein the disease is bovine spongiform encephalopathy.  
     
     
         18 . A method of detecting a prion PrP protein disease, the method comprising: 
 contacting the inhibitory peptide of  claim 3  with a prion PrP protein of a subject;    binding the inhibitory peptide to a prion PrP protein; and    visualizing binding of the inhibitory peptide to the prion PrP protein.