Pleiotropic mechanisms of ribavirin antiviral activities

Renewed interest in the mechanism of action of ribavirin results from its synergistic enhancement of interferon therapy and the need to develop more efficacious agents to treat hepatitis C virus infection. Since the discovery of ribavirin over 30 years ago by scientists at ICN Pharmaceuticals, many mechanisms of action for ribavirin have been proposed. These include inhibition of host inosine monophosphate dehydrogenase by ribavirin monophosphate, inhibition of viral capping enzymes, inhibition of viral RNA synthesis by ribavirin triphosphate, lethal mutagenesis of viral RNA genomes resulting from promiscuous incorporation of ribavirin triphosphate by the viral RNA polymerase, and modulation of the host immune responses. In this article, we will briefly review the evidence for these mechanisms, emphasizing recent findings. In addition, we will discuss strategies for development of nucleoside analogs that may replace ribavirin in the future.