Hepatitis C virus RNA-directed RNA polymerase NS5B (NS5B) (NS5B)

The Hepatitis C virus (HCV) RNA-directed RNA polymerase NS5B is the essential catalytic enzyme responsible for replicating the viral RNA genome (UniProt: P26664). It belongs to the viral RNA-directed RNA polymerase family and adopts a characteristic "right-hand" fold with fingers, palm, and thumb domains that coordinate the synthesis of positive-sense RNA (PubMed: 15576067). As a central component of the viral replication machinery, NS5B is a validated therapeutic target for direct-acting antivirals (DAAs) used to treat chronic Hepatitis C (NIH). Inhibitors of NS5B are categorized into nucleoside/nucleotide analogs, such as Sofosbuvir, which cause premature chain termination, and non-nucleoside inhibitors, such as Dasabuvir, which bind to allosteric sites to prevent the conformational changes necessary for RNA synthesis (PubMed: 25514087). These therapies have significantly improved sustained virologic response (SVR) rates in patients, although the development of resistance-associated substitutions (RASs) can impact efficacy (PubMed: 28264431). Clinical use requires monitoring for drug-drug interactions and specific safety risks, such as severe bradycardia when certain NS5B inhibitors are co-administered with amiodarone (FDA).

Other names

NS5BHCV RdRpNon-structural protein 5BRNA-directed RNA polymeraseHCV RNA-dependent RNA polymeraseHCV viral RNA synthesis machineryHCV replication complex

Inhibition of viral RNA synthesis through either competitive incorporation into the nascent RNA chain leading to chain termination (nucleoside/nucleotide analogs) or allosteric binding to the enzyme surface to prevent conformational changes required for catalysis (non-nucleoside inhibitors).