Nonstructural protein 5B (Hepatitis C virus) (NS5B)

Nonstructural protein 5B (NS5B) is an RNA-dependent RNA polymerase (RdRp) that serves as the catalytic core of the Hepatitis C virus (HCV) replication complex [1.2.1, 1.3.1]. It is responsible for synthesizing new viral RNA strands by using the positive-sense genomic RNA as a template to create a negative-sense intermediate, which then directs the production of progeny genomes [1.4.1, 1.4.2]. Structurally, NS5B adopts a classic 'right hand' polymerase fold consisting of finger, palm, and thumb subdomains that encircle the active site [1.2.2, 1.2.3]. Because humans lack a direct functional equivalent of this enzyme, it is a highly selective target for direct-acting antiviral (DAA) drugs, which offer minimal off-target effects [1.1.3, 1.2.1]. These drugs are categorized into nucleoside inhibitors (NIs), which act as chain terminators, and non-nucleoside inhibitors (NNIs), which bind to allosteric sites to inhibit the enzyme's conformational changes [1.2.2, 1.3.1]. The clinical success of NS5B inhibitors like sofosbuvir has transformed the treatment of chronic hepatitis C, enabling high rates of sustained virologic response (SVR) across various genotypes [1.2.1, 1.4.2].

Other names

NS5B polymeraseRNA-dependent RNA polymeraseRdRpHCV NS5Bp75

Nucleoside inhibitors (NIs) act as chain terminators by mimicking natural substrates and being incorporated into the nascent RNA strand, while non-nucleoside inhibitors (NNIs) bind to allosteric sites on the enzyme to induce conformational changes that inhibit polymerase activity.