Screening molecules with anti-prion activity: kits, methods and screened molecules

Abstract

A kit and a method for identifying compounds having anti-prion activity are provided. The kit comprises a yeast of phenotype [PSI+]; an antibiogram; and a prion curing agent in a sub-effective dose, wherein the yeast has the adel-14 allele of the ADE1 gene and an inactivated ERG6 gene. Compounds and pharmaceutical compositions having anti-prion activity are also provided, which are useful for treating various neurodegenerative diseases, including polyglutamines expansion associated diseases; Huntington's disease; Kennedy disease; amyotrophic lateral sclerosis; cerebellous autosomic ataxies; dentalorubral-pallidoluysian atrophy; and spino-bulbar amyotrophy.

1 . A method for treating neurodegenerative diseases involving protein aggregates, the method comprising:
 administering the compound of formula (I)   
       
         
           
           
               
               
           
         
         wherein R′ is an H, NH 2 , NHR 2  group, where R 2  is an alkyl or alkylaminoalkyl chain with 1 to 10 carbon atoms, branched or unbranched, 
         X represents F, Cl, Br, I, CF 3 , SCH 3 , OCH 3 , OH, NO 2 , COCH 3 , CONH 2 , COOH, COOR 3 , where R 3  is an alkyl group with 1 to 4 carbon atoms, 
         p and n, identical or different, are equal to 0, 1 or 2, 
         q is equal to 0 or 1. 
       
     
     
         2 . A method for treating neurodegenerative diseases involving protein aggregates, the method comprising:
 administering the compound of formula (III)   
       
         
           
           
               
               
           
         
       
       wherein R′ represents an H, NH 2 , NH—(CH 2 ) 3 —N(CH 3 ) 2 , NH—CH(CH 3 )—(CH 2 ) 3 —N(CH 2 —CH 3 ) 2  group,
 X represents F, Cl, CF 3 , 
 
       p and n, identical or different, are equal to 0, 1 or 2. 
     
     
         3 . A method for treating neurodegenerative diseases involving protein aggregates, the method comprising:
 administering the compound of formula (II)   
       
         
           
           
               
               
           
         
         wherein R represents an H, NH 2 , NH—(CH 2 ) 3 —N(CH 3 ) 2 , NH—CH(CH 3 )—(CH 2 ) 3 —N(CH 2 —CH 3 ) 2  group, 
         X represents F, Cl, CF 3 , 
         p and n, identical or different, are equal to 0, 1 or 2. 
       
     
     
         4 . A method for treating neurodegenerative diseases involving protein aggregates, the method comprising:
 administering the compound of formula (II)   
       
         
           
           
               
               
           
         
         wherein R′ represents an NH 2  group, 
         X represents F, Cl, CF 3 , 
         p and n, identical or different, are equal to 0, 1 or 2. 
       
     
     
         5 . The method of claim  11 , wherein the neurodegenerative diseases include: spongiform encephalopathies, Alzheimer's disease, and Huntington's disease. 
     
     
         6 . The method of claim  12 , wherein the neurodegenerative diseases include: spongiform encephalopathies, Alzheimer's disease, and Huntington's disease. 
     
     
         7 . The method of claim  13 , wherein the neurodegenerative diseases include: spongiform encephalopathies, Alzheimer's disease, and Huntington's disease. 
     
     
         8 . The method of claim  13 , wherein the neurodegenerative diseases include:
 polyglutamines expansion associated diseases;   Huntington's disease;   Kennedy disease;   the amyotrophic lateral sclerosis;   cerebellous autonomic ataxies;   dentalorubral-pallidoluysian atrophy; and   spino-bulbar amyotrophy.