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

The Hepatitis C virus (HCV) nonstructural protein 5B (NS5B) is a 66 kDa membrane-associated enzyme that serves as the RNA-dependent RNA polymerase (RdRp) essential for the replication of the viral genome (UniProt: P26664). It functions within a multi-protein replication complex alongside other nonstructural proteins like NS3 (protease/helicase), NS4A (cofactor), and NS5A (phosphoprotein), which together constitute the viral replication machinery localized on the host's membranous web (PubMed: 25135993). NS5B catalyzes the synthesis of a negative-strand RNA intermediate from the positive-strand genomic RNA, which then serves as a template for producing new positive-strand genomes (NIH: StatPearls). Because humans lack a homologous RdRp, NS5B and its associated proteins are highly selective and effective targets for direct-acting antivirals (DAAs). Therapeutic strategies include nucleoside/nucleotide analogs like sofosbuvir that cause premature RNA chain termination and non-nucleoside inhibitors like dasabuvir that bind to allosteric sites to prevent conformational changes (PubChem: CID 45375808). These drugs are typically used in combination with NS5A and NS3/4A inhibitors to achieve sustained virologic response (SVR) and minimize the emergence of drug resistance (Wikipedia: Hepatitis C virus).

Other names

HCV RNA-dependent RNA polymeraseRdRpHCV replication complexNS5B polymeraseNon-structural protein 5B

Inhibition of viral RNA synthesis via chain termination or allosteric inhibition of the NS5B polymerase, and disruption of the NS5A and NS3/4A components of the replication complex.