Hepatitis C virus nonstructural protein 5B RNA-dependent RNA polymerase (Thumb-1 allosteric site) (HCV NS5B Thumb-1 site)

The Thumb-1 allosteric site is a regulatory pocket located on the thumb domain of the Hepatitis C virus (HCV) nonstructural protein 5B (NS5B), which functions as the RNA-dependent RNA polymerase (RdRp) responsible for replicating the viral genome (Tomei et al., 2005, PubMed: 16135246). This site is a primary target for non-nucleoside inhibitors (NNIs), which bind to the enzyme at a location distal to the catalytic active site. Binding at the Thumb-1 site stabilizes the polymerase in an inactive conformation, preventing the essential structural transition from the initiation phase to the elongation phase of RNA synthesis (Beaulieu, 2009, PubMed: 19450130). This mechanism effectively blocks the production of new viral RNA strands, making it a key component in direct-acting antiviral (DAA) strategies for treating chronic Hepatitis C. While potent, inhibitors targeting this site often face challenges such as a low genetic barrier to resistance and high specificity for certain HCV genotypes, particularly genotype 1 (Di Marco et al., 2005, PubMed: 15939857). Consequently, these drugs are typically developed for use in combination therapy to ensure sustained virologic response and prevent the selection of resistant viral variants.

Other names

NS5B Thumb-1 pocketAllosteric site 1HCV NS5B polymerase Thumb-1 domainNon-nucleoside inhibitor site 1Thumb-I allosteric pocket

Non-nucleoside inhibition (NNI) through binding to the Thumb-1 allosteric pocket, which stabilizes the polymerase in an inactive conformation and prevents the transition from the initiation to the elongation phase of RNA synthesis.