The hepatitis C virus replicase: Insights into RNA-dependent RNA replication and prospects for rational drug design

The enzymes involved in the replication of the Hepatitis C Virus (HCV) have been some of the most intensely studied proteins in recent history because they are targets for rational drug design. HCV is an established and growing menace to human health that is without a current vaccine or a widely affordable and effective treatment. Traditional antiviral screening is difficult with HCV because of the lack of a convenient animal model or tissue culture system. Consequently, two viral replicative proteins have been intensely studied as drug targets: the NS3 protein, which possesses serine protease, ATPase, and helicase activities, and the NS5B RNA-dependent RNA polymerase. Structural and mechanistic studies of the HCV replicative proteins have not yet led to antiviral HCV drugs. However, new insights have been gained into the mechanisms of actions of the enzymes comprising the viral replicase. This review discusses recent advances in understanding the HCV NS5B RNA-dependent RNA polymerase and the NS3 helicase mechanisms and suggests how this new information could be exploited for the potential development of future antiviral agents.