Hepatitis C virus RNA-dependent RNA polymerase and host inosine monophosphate dehydrogenase (HCV NS5B and IMPDH)

The target complex consists of the Hepatitis C virus (HCV) non-structural protein 5B (NS5B), which is an RNA-dependent RNA polymerase (RdRp), and the host cell enzyme inosine monophosphate dehydrogenase (IMPDH). NS5B is essential for the replication of the HCV RNA genome, serving as the catalytic subunit that synthesizes new RNA strands using the viral RNA template (UniProt P26663). IMPDH is a key host enzyme that regulates the de novo pathway of guanine nucleotide biosynthesis by converting inosine monophosphate to xanthosine monophosphate (UniProt P12268). Drugs like ribavirin target this dual system; by inhibiting host IMPDH, they deplete intracellular GTP pools, which subsequently enhances the incorporation of ribavirin triphosphate by NS5B into the nascent viral RNA (PubMed 11154699). This dual action leads to the inhibition of viral replication and the induction of lethal mutagenesis, often referred to as error catastrophe, in the viral population. This combination is primarily relevant in the treatment of chronic Hepatitis C infection, where host metabolic modulation supports direct antiviral activity.

Other names

NS5BIMPDHHCV RdRpInosine-5'-monophosphate dehydrogenaseHepatitis C virus non-structural protein 5BIMPDH1IMPDH2

Inhibition of host IMPDH leads to GTP depletion, while inhibition of HCV NS5B prevents viral RNA synthesis and induces lethal mutagenesis.