Hepatitis C virus nonstructural protein 5B RNA-dependent RNA polymerase (NS5B) (NS5B)

The Hepatitis C virus (HCV) nonstructural protein 5B (NS5B) is an RNA-dependent RNA polymerase (RdRp) essential for the replication of the viral genome (UniProt: P26663). It functions by using the positive-sense viral RNA as a template to catalyze the synthesis of a negative-sense RNA intermediate, which then serves as a template for new genomic RNA (PubMed: PMC4392858). Because humans lack a homologous RdRp, NS5B is a highly specific and effective therapeutic target for treating chronic Hepatitis C (StatPearls: NBK542210). Drugs like sofosbuvir act as nucleotide analogs that are phosphorylated intracellularly to an active triphosphate form; this metabolite competes with natural nucleotides for incorporation into the viral RNA, causing premature chain termination (PubChem: CID 45375808). Other classes of inhibitors, such as dasabuvir, are non-nucleoside inhibitors (NNIs) that bind to allosteric sites on the enzyme, inducing conformational changes that inhibit polymerase activity (PubMed: PMC4382314). Targeting NS5B has revolutionized Hepatitis C therapy, enabling high cure rates and shorter treatment durations across multiple viral genotypes.

Other names

NS5BRNA-directed RNA polymeraseHCV NS5BHepatitis C virus RNA-directed RNA polymeraseRdRp

Sofosbuvir is a nucleotide analog prodrug that is metabolized into its active triphosphate form (GS-461203), which competes with natural nucleotides for incorporation into the nascent viral RNA strand by the NS5B polymerase, leading to premature chain termination (StatPearls: NBK542210). Non-nucleoside inhibitors (NNIs) like dasabuvir bind to allosteric sites on the enzyme to induce conformational changes that prevent RNA synthesis (PubMed: PMC4382314).