Nonstructural protein 5B RNA-directed RNA polymerase (NS5B) (NS5B)

Nonstructural protein 5B (NS5B) is a 68 kDa membrane-associated protein that functions as the RNA-dependent RNA polymerase (RdRp) for the Hepatitis C virus (HCV) [1, 2]. It is the central catalytic component of the viral replication complex, responsible for synthesizing new viral RNA genomes from a positive-strand RNA template [2]. The protein's structure resembles a right hand with fingers, palm, and thumb domains, which coordinate the binding of the RNA template and nucleotide triphosphates [2, 5]. Because there is no human homolog for this viral enzyme, NS5B is a primary target for direct-acting antiviral (DAA) therapies, offering high specificity and minimal off-target effects [4]. Therapeutic strategies include the use of nucleotide analogs like sofosbuvir that cause premature chain termination and non-nucleoside inhibitors like dasabuvir that bind to allosteric sites to block the enzyme's activity [3, 4]. Successful inhibition of NS5B is a cornerstone of modern HCV treatment regimens, leading to high rates of sustained virologic response [4, 6].

Other names

HCV NS5BRNA-dependent RNA polymerase NS5Bp68NS5B polymeraseHepatitis C virus nonstructural protein 5B

NS5B inhibitors function through two primary mechanisms: nucleoside/nucleotide analogs (NIs) act as chain terminators by mimicking natural substrates and being incorporated into the growing RNA strand, while non-nucleoside inhibitors (NNIs) bind to allosteric sites (e.g., palm or thumb domains) on the enzyme to induce conformational changes that inhibit catalytic activity [2, 4].