Infections caused by hepatitis C virus (HCV) are a significant worldwide health problem for which novel therapies are urgently needed. One attractive and viable therapeutic target is HCV NS5B RNA dependent RNA polymerase (RdRp) since it is essential for the replication of the viral genome of HCV. The hunt for nonnucleoside inhibitors (NNIs) of HCV NS5B polymerase has led to the identification of several allosteric pockets. However, because the topographical features of these binding sites vary across and even within diverse HCV genotypes, the discovery of new antiviral drugs capable of inhibiting HCV RdRp in the face of variable binding pockets becomes a challenging endeavor. This review focuses on recent accomplishments in the development of new NNIs of HCV NS5B polymerase and on their binding mechanisms to the respective allosteric pockets. Potential difficulties surrounding the discovery of future NNIs targeted to different allosteric pockets of HCV NS5B and to HCV NS5B from different genotypes are also discussed.
Keywords: HCV NS5B polymerase, Allosteric pocket, Nonnucleoside inhibitors, Genotypes, Structure activity relationships