Hepatitis C virus non-structural protein 5B RNA-dependent RNA polymerase (HCV NS5B RdRp)

The Hepatitis C virus (HCV) non-structural protein 5B (NS5B) is an RNA-dependent RNA polymerase (RdRp) that serves as the catalytic engine for viral genome replication (UniProt: P26663). It is responsible for synthesizing a negative-strand RNA from the positive-strand genomic template, which then acts as a scaffold for producing numerous progeny positive-strand RNAs. Structurally, NS5B adopts a "right-hand" conformation consisting of fingers, palm, and thumb domains that coordinate the entry of nucleotides and the RNA template. Ribavirin, a broad-spectrum antiviral guanosine analog, interacts with NS5B and is incorporated into the nascent RNA strand, causing an accumulation of mutations that leads to "lethal mutagenesis" of the virus (PMID: 11565027). While modern direct-acting antivirals (DAAs) like sofosbuvir target NS5B with higher specificity and potency as chain terminators, ribavirin's interaction remains clinically significant in combination therapies for difficult-to-treat genotypes. Targeting NS5B is a cornerstone of HCV therapy, as its inhibition effectively halts the production of new viral particles and can lead to a complete cure of the infection. The enzyme's active site is highly conserved, though specific resistance-associated substitutions can impact drug efficacy (PMID: 24755471).

Other names

NS5BHCV NS5BRNA-directed RNA polymeraseHCV polymeraseNon-structural protein 5B

Ribavirin acts as a nucleoside analog that is incorporated into viral RNA by NS5B, leading to lethal mutagenesis or direct inhibition of RNA synthesis (PMID: 11565027). Other drugs like sofosbuvir act as obligate chain terminators (PMID: 24755471).