Compositions and Methods for the Treatment of Norovirus Infection

Abstract

Compositions and methods for the treatment of norovirus infection are disclosed.

1 . (canceled) 
     
     
         2 . A viral RNA polymerase inhibitor for the treatment of norovirus infection having the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 X 1  and X 2  are independently C, NH, O, or S; 
 R 1  is selected from the group consisting of a carboxylic acid, a carboxylate ester, an amide, and an aldehyde group; 
 R 2  is a saturated or unsaturated hydrocarbon selected from the group consisting of straight and branched chain alkyl, which has 1 to about 20 carbons and which may be interrupted with at least one oxygen, nitrogen, or sulfur, alkenyl, alkynyl, cycloalkyl, and aryl; 
 R 3  is a lower alkyl, H, or ═O; 
 R 4  is a saturated or unsaturated hydrocarbon selected from the group consisting of straight or branched chain alkyl, which has 1 to about 20 carbons and which may be interrupted with at least one oxygen, nitrogen, or sulfur, alkenyl, alkynyl, cycloalkyl, cycloakyl, and aryl; and 
 R 5  is a saturated or unsaturated hydrocarbon selected from the group consisting of straight and branched chain alkyl, which has 1 to about 20 carbons and which may be interrupted with at least one oxygen, nitrogen, or sulfur, alkenyl, alkynyl, cycloakyl, and aryl. 
 
     
     
         3 . A norovirus RNA polymerase inhibitor as claimed in  claim 2  selected from the group of compounds shown in  FIG. 3 . 
     
     
         4 . A norovirus RNA polymerase inhibitor as claimed in  claim 2 , wherein R 1  is selected from the group consisting of a carboxylic acid, a carboxylate ester, and an amide. 
     
     
         5 . A pharmaceutical composition comprising at least one of the compounds of  claim 2  or  claim 4  or a pharmaceutically acceptable salt or prodrug thereof and one or more pharmaceutically acceptable excipients. 
     
     
         6 . (canceled) 
     
     
         7 . A method for identifying agents which modulate norovirus RNA polymerase activity associated with clinical pathology comprising:
 a) incubating cells expressing said viral RNA polymerase and at least one innate immune receptor and a reporter gene operably linked to an interferon beta promoter in the presence and absence of a test agent, wherein in synthesis of viral RNA from said RNA polymerase triggers a cellular defense response which is effective to activate expression of said reporter gene; and   b) measuring reporter gene expression in the presence and absence of said agent, alterations of said reporter gene expression in the presence of said agent being indicative of RNA polymerase modulatory activity.   
     
     
         8 . The method of  claim 7 , wherein said innate immune receptor is selected from the group consisting of RIG-1 and MDA5. 
     
     
         9 . The method of  claim 7 , wherein said reporter gene is luciferase. 
     
     
         10 . The method of  claim 7 , wherein said cellular defense response comprises production of RIG-1 ligands. 
     
     
         11 . The method of  claim 7  comprising co-expression of norovirus VPg or a variant thereof. 
     
     
         12 . The method of  claim 7 , wherein said cells are selected from the group consisting of 293T cells, Huh7 and macrophage cells. 
     
     
         13 . The method of  claim 7 , wherein said agent is a non-nucleoside inhibitor or a nucleoside analog. 
     
     
         14 . The method of  claim 7  comprising co-expression of additional norovirus proteins. 
     
     
         15 . The norovirus RNA polymerase inhibitor as claimed in  claim 2 , wherein said alkyl is lower alkyl.