Hepatitis C virus non-structural protein 5B (NS5B) (NS5B)

The Hepatitis C virus non-structural protein 5B (NS5B) is an essential RNA-dependent RNA polymerase (RdRp) responsible for replicating the viral RNA genome (UniProt P26664). It functions by using the positive-sense viral RNA strand as a template to synthesize a negative-sense intermediate, which then serves as a template for new genomic RNA (PubMed: 11581170). Because humans lack a homologous RdRp enzyme, NS5B is a highly selective and effective target for antiviral therapy (StatPearls: Hepatitis C). Drugs targeting NS5B are classified into nucleoside/nucleotide inhibitors (NIs), which act as chain terminators, and non-nucleoside inhibitors (NNIs), which bind to allosteric sites to induce conformational changes (PubMed: 25514044). Sofosbuvir, a prominent NI, has revolutionized treatment by providing a high barrier to resistance and pan-genotypic activity (NIH: LiverTox). Targeting this enzyme is critical for achieving a sustained virologic response (SVR) and curing chronic Hepatitis C infection (PubMed: 24140009).

Other names

HCV RNA-dependent RNA polymeraseNS5B polymeraseNon-structural protein 5BHCV RdRpRNA-directed RNA polymerase

NS5B inhibitors work through two primary mechanisms: nucleoside/nucleotide analogs (NIs) mimic natural substrates and cause premature RNA chain termination once incorporated into the growing viral RNA strand, while non-nucleoside inhibitors (NNIs) bind to one of four allosteric thumb or palm domains, preventing the enzyme from adopting a catalytically active conformation (PubMed: 25514044).