Non-nucleoside inhibitors of the HCV NS5B polymerase: progress in the discovery and development of novel agents for the treatment of HCV infections.

The severe health conditions associated with chronic HCV infection remain a global concern. Small-molecule drugs that specifically target essential virally encoded enzymes have not yet progressed to market, and the current standard of care continues to rely on a combination of pegylated IFN with ribavirin. This therapy has serious side effects and a significant proportion of patients infected with HCV genotype 1 (the major genotype in industrialized countries) have an unsatisfactory outcome with this therapy. Major advances have been realized in the development of specific non-nucleoside inhibitors of the viral NS5B RNA-dependent RNA polymerase. This well-characterized replicative enzyme is a highly drugable target that, in addition to its active site, features at least three known allosteric binding pockets that regulate RNA synthesis and are suitable for inhibitor design. Clinical proof-of-concept for allosteric non-nucleoside HCV polymerase inhibitors has been reported and several compounds have progressed into preclinical studies. It is likely that in the future NS5B inhibitors will form an integral part of more effective anti-HCV therapies, combining the use of small-molecule antiviral drugs with or without the assistance of immune modulators such as IFNs in order to minimize the emergence of resistance.