Hepatitis C virus NS5B RNA-dependent RNA polymerase (thumb I allosteric site) (HCV NS5B RdRp (Thumb I))

The Hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase is the essential enzyme for the replication of the HCV RNA genome, making it a primary target for direct-acting antiviral (DAA) therapy (UniProt P26664). The enzyme adopts a structure resembling a right hand, with palm, fingers, and thumb domains that coordinate to synthesize new RNA strands (PubMed: 10567577). The thumb I allosteric site is a specific pocket located at the top of the thumb domain, which plays a crucial role in the enzyme's conformational dynamics (PubMed: 24125048). Non-nucleoside inhibitors (NNIs) that bind to this site prevent the polymerase from shifting from its initiation state to its productive elongation state, effectively blocking viral replication (PubMed: 15930557). Although potent, inhibitors of the thumb I site are often limited by their narrow spectrum of activity across different HCV genotypes and a relatively low genetic barrier to resistance (PubMed: 23539134).

Other names

NS5BRNA-directed RNA polymeraseHCV RdRpNon-structural protein 5BThumb I pocket

Non-nucleoside inhibition of RNA-dependent RNA polymerase by binding to the thumb I allosteric pocket, preventing the conformational shift from initiation to elongation.