Approaching a new era for hepatitis C virus therapy: inhibitors of the NS3-4A serine protease and the NS5B RNA-dependent RNA polymerase

The treatment of chronic disease caused by the hepatitis C virus (HCV) is an unmet clinical need, since current therapy is only partially effective and limited by undesirable side effects. The viral serine protease and the RNA-dependent RNA polymerase are the best-studied targets for the development of novel therapeutic agents. These enzymes have been extensively characterized at the biochemical and structural level and thus used to set up screening assays for the identification of selective inhibitors. These efforts lead to the discovery of several classes of compounds with potential antiviral activity. The hepatitis C virus does not replicate in the laboratory. The formidable challenge posed by the difficulty of developing cell-based assays and preclinical animal systems has been partially overcome with several alternative approaches. The development of new assays permitted the optimization of enzyme inhibitors leading eventually to molecules with the desired drug-like properties, the most advanced of which are being considered for clinical trials.