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

The Hepatitis C virus (HCV) nonstructural protein 5B (NS5B) is an RNA-directed 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 synthesize a negative-sense RNA intermediate, which then serves as a template for producing new genomic RNA (PubMed: 11581170). Structurally, NS5B adopts a right-hand conformation consisting of palm, fingers, and thumb domains, which are characteristic of many polymerases (PubMed: 10503929). Because humans lack a direct homolog of this viral enzyme, NS5B is a highly attractive and validated therapeutic target for treating chronic Hepatitis C (StatPearls: Hepatitis C). Drugs targeting NS5B are generally classified into two categories: nucleoside/nucleotide analogs (NIs) that act as chain terminators and non-nucleoside inhibitors (NNIs) that bind to allosteric sites to induce conformational changes (PubChem: Sofosbuvir). Sofosbuvir, a prominent NI, has revolutionized treatment by providing high cure rates across multiple genotypes (NIH: LiverTox). However, the emergence of resistance-associated substitutions and potential drug-drug interactions remain key considerations in clinical management (PubMed: 26231133). The enzyme's high error rate contributes to the genetic diversity of HCV, necessitating combination therapies to prevent the selection of resistant variants (PubMed: 18328403).

Other names

NS5BNS5B polymeraseRNA-dependent RNA polymeraseRdRpHCV RdRpHepatitis C virus RNA-directed RNA polymerase

Nucleoside/nucleotide analog inhibition (obligate chain termination) and non-nucleoside allosteric inhibition (binding to palm, thumb, or finger domains to prevent conformational changes required for catalysis) (PubMed: 24128545).