Compounds For Treating Human Papillomavirus

Abstract

Methods and compositions for treating human papillomavirus infections are described.

1 . A method for treating a human papillomavirus (HPV) infection in a subject, the method comprising:
 administering to a subject in need thereof a composition comprising a compound of formula (I) in an amount effective to inhibit HPV activity, wherein the compound of formula (I) is:   
       
         
           
           
               
               
           
         
         and wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are each, independently, selected from the group consisting of hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl, alkoxy, haloalkoxy, halo, hydroxy, carboxy, carboxylate, formyl, acyl, cyano, nitro, amino, alkyl amino, SO 3 H, sulfate, phosphate, methylenedioxy, ethylenedioxy, oxo, thioxo, imino, S(O) n alkyl, S(O) n  aryl, S(O) n  heteroaryl, S(O) n  heterocyclyl, amine, ester, amide, and sulfonamide; 
         Ar is selected from the group consisting of aryl and heteroaryl; 
         R 8  is selected from the group consisting of hydrogen and C 1 -C 10  alkyl; and 
         X is selected from the group consisting of S and O. 
       
     
     
         2 . The method of  claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  is each a hydrogen bond donor moiety. 
     
     
         3 . The method of  claim 1 , wherein R 1  is a hydrogen bond donor moiety; R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are each hydrogen; X is O; Ar is aryl; and R 8  is selected from the group consisting of a C 1 -C 10  alkyl. 
     
     
         4 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 1 , wherein the subject has a condition selected from the group consisting of common warts, anal warts, oral warts, pharyngeal warts, laryngeal warts, genital warts, an HPV-induced dysplasia, an HPV-induced cancer, and epidermodysplasia verruciformis. 
     
     
         6 . The method of  claim 1 , wherein the composition further comprises a pharmaceutically acceptable carrier or adjuvant. 
     
     
         7 . The method of  claim 1 , wherein the composition is administered orally, parenterally, topically, or by inhalation. 
     
     
         8 . A method of identifying a compound that inhibits the activity of the HPV 16 E6 protein, the method comprising:
 (a) providing a compound of formula (I):   
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are each, independently, selected from the group consisting of hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl, alkoxy, haloalkoxy, halo, hydroxy, carboxy, carboxylate, formyl, acyl, cyano, nitro, amino, alkyl amino, SO 3 H, sulfate, phosphate, methylenedioxy, ethylenedioxy, oxo, thioxo, imino, S(O) n alkyl, S(O) n  aryl, S(O) n  heteroaryl, S(O) n  heterocyclyl, amine, ester, amide, and sulfonamide; 
         Ar is selected from the group consisting of aryl and heteroaryl; 
         R 8  is selected from the group consisting of hydrogen and C 1 -C 10  alkyl; and 
         X is selected from the group consisting of S and O; and 
         (b) determining whether the compound blocks the interaction of E6 and a protein containing an E6 binding motif, wherein the compound is identified as inhibiting the activity of the HPV 16 E6 protein if the compound blocks the interaction of E6 and the protein containing an E6 binding motif, compared to a control. 
       
     
     
         9 . The method of  claim 8 , wherein the protein containing an E6 binding motif is E6BP protein or E6AP protein. 
     
     
         10 . The method of  claim 9 , wherein determining whether the compound blocks the interaction of E6 and the E6BP protein or the E6AP protein comprises analyzing the binding of E6 and E6BP or E6AP in vitro, (i) in the presence of the compound, and (ii) in the presence of the control. 
     
     
         11 . The method of  claim 8 , wherein determining whether the compound blocks the interaction of E6 and the protein containing an E6 binding motif comprises analyzing p53 degradation in vitro, and wherein a compound that inhibits p53 degradation to a greater level than a control is identified as a compound that inhibits the activity of the HPV 16 E6 protein. 
     
     
         12 . The method of  claim 11 , wherein a compound that has an IC50 for inhibition of p53 degradation between 1 and 2 μM is identified as a compound that inhibits the activity of the HPV 16 E6 protein. 
     
     
         13 . A method of identifying a chemical derivative that inhibits the activity of the HPV 16 E6 protein, the method comprising:
 (a) providing a compound, wherein the compound is:   
       
         
           
           
               
               
           
         
         (b) generating a chemical derivative of the compound; and 
         (c) determining whether the chemical derivative blocks the interaction of E6 and a protein containing an E6 binding motif, wherein the chemical derivative is identified as inhibiting the activity of the HPV 16 E6 protein if the chemical derivative blocks the interaction of E6 and the protein containing an E6 binding motif, compared to a control. 
       
     
     
         14 . The method of  claim 13 , wherein determining whether the chemical derivative blocks the interaction of E6 and the protein containing an E6 binding motif comprises analyzing the binding of E6 and E6BP in vitro. 
     
     
         15 . The method of  claim 13 , wherein determining whether the chemical derivative blocks the interaction of E6 and the protein containing an E6 binding motif comprises analyzing p53 degradation.