Antiviral prodrugs and nanoformulations thereof

Abstract

The present invention provides prodrugs and methods of use thereof.

1 - 36 . (canceled) 
     
     
         37 . A compound, or a pharmaceutically acceptable salt thereof, comprising a first integrase inhibitor and a second integrase inhibitor, wherein said first and second integrase inhibitors are covalently attached by a linker. 
     
     
         38 . The compound of  claim 37 , wherein said first and second integrase inhibitors are each independently selected from the group consisting of cabotegravir (CAB), raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG), bictegravir (BIC), BI 224436, and MK-2048. 
     
     
         39 . The compound of  claim 37 , wherein said linker is an optionally substituted aliphatic group, and wherein said linker forms an ester with the oxygen of a hydroxyl moiety of said first and second integrase inhibitors. 
     
     
         40 . The compound of  claim 39 , wherein said optionally substituted aliphatic group comprises 1 to 30 carbons. 
     
     
         41 . The compound of  claim 37 , wherein the compound is represented by Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V): 
       
         
           
           
               
               
           
         
         wherein the —(CH 2 ) n — of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) is optionally substituted with at least one heteroatom; and 
         n is an integer from 1 to 24. 
       
     
     
         42 . The compound of  claim 41 , wherein n is an integer from 6 to 14. 
     
     
         43 . The compound of  claim 37 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         44 . A compound, or a pharmaceutically acceptable salt thereof, comprising an integrase inhibitor conjugated to an amino acid fatty ester, wherein the amino acid fatty ester comprises an aliphatic group. 
     
     
         45 . The compound of  claim 44 , wherein said integrase inhibitor is selected from the group consisting of cabotegravir (CAB), raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG), bictegravir (BIC), BI 224436, and MK-2048. 
     
     
         46 . The compound of  claim 44 , wherein the compound is represented by Formula (VI), Formula (VII), Formula (VIII), Formula (IX), or Formula (X): 
       
         
           
           
               
               
           
         
         wherein: 
         R is an optionally substituted aliphatic group; and 
         AA is one or more amino acids. 
       
     
     
         47 . The compound of  claim 46 , wherein AA is one amino acid. 
     
     
         48 . The compound of  claim 46 , wherein AA is selected from the group consisting of alanine, valine, phenylalanine, proline, tyrosine, and lysine. 
     
     
         49 . The compound of  claim 46 , wherein R is a saturated linear aliphatic chain of a length of 11 to 19 carbons. 
     
     
         50 . The compound of  claim 44 , wherein said compound is 
       
         
           
           
               
               
           
         
       
     
     
         51 . A nanoparticle, comprising a compound or a pharmaceutically acceptable salt thereof of  claim 37 , and at least one polymer or surfactant. 
     
     
         52 . The nanoparticle of  claim 51 , wherein said polymer or surfactant is an amphiphilic block copolymer. 
     
     
         53 . The nanoparticle of  claim 52 , wherein said amphiphilic block copolymer comprises at least one block of poly(oxyethylene) and at least one block of poly(oxypropylene). 
     
     
         54 . The nanoparticle of  claim 51 , wherein the polymer or surfactant is P407. 
     
     
         55 . A pharmaceutical composition, comprising a compound or a pharmaceutically acceptable salt thereof of  claim 37 , and at least one pharmaceutically acceptable carrier. 
     
     
         56 . A method of treating a viral infection in a subject in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition of  claim 55  to the subject. 
     
     
         57 . The method of  claim 56 , wherein the viral infection is an HIV infection.