Non-hydrolysable analogues of inorganic pyrophosphate as inhibitors of hepatitis C virus RNA-dependent RNA-polymerase

Abstract

Inorganic pyrophosphate (PPi) is a product of the polymerization reaction catalyzed by DNA- and RNA-polymerases. We have synthesized a number of novel non-hydrolysable PPi analogues, some of them have demonstrated inhibition of polymerization reaction catalyzed by hepatitis C virus RNA-dependent RNA-polymerase (NS5B). A new pharmacophore has been developed based on non-hydrolysable methylene-diphosphonate backbone. Structure-activity relationship analysis of 12 bisphosphonates is presented and structural features crucial for the ability of molecule to inhibit NS5B polymerase activity are ascertained.