Nucleoside Analog Inhibitors of Hepatitis C Virus Replication

S.   S.   Carroll; D.   B.   Olsen

Abstract

Of the 30 compounds currently marketed in the United States for treatment of viral infections, 15 are nucleoside analogs, demonstrating the utility of this class of compound as a source of antiviral drugs. The success of nucleoside analogs in treating other viral infections provides a compelling rationale for the significant effort that is currently being devoted to the discovery and development of nucleoside analogs to treat infection by hepatitis C virus (HCV) that may lead to improvements in response rates compared to currently available therapies. Several different approaches have been adopted to identify promising analogs, including the use of surrogate viruses in cell culture assays, screening in the cell-based bicistronic HCV replicon assay, and screening nucleoside triphosphates for the ability to inhibit the activity of the HCV RNA-dependent RNA polymerase in vitro. Several classes of ribonucleoside analogs with modifications of the ribose inhibit HCV replication. Nucleoside analogs incorporating a 2-C-methyl modification are potent inhibitors in the replicon assay in the absence of cytotoxicity, and appear to exert their inhibition by acting as functional chain terminators of RNA synthesis. NM283, a prodrug of 2-C-methylcytidine, has entered clinical trials and demonstrated viral load reductions in subjects infected with genotype 1 HCV, a genotype known to be difficult to treat effectively with currently approved therapies. Overall, results to date offer encouragement that improved therapies to treat HCV infection including newly developed nucleoside analogs may become available within the next few years.

Keywords: Nucleoside analog, replicon, structure-activity relationships, RNA polymerase, chain terminator