Hepatitis C virus non-structural protein 5B (NS5B) and host inosine-5'-monophosphate dehydrogenase (IMPDH) (HCV NS5B & IMPDH)

Hepatitis C virus (HCV) non-structural protein 5B (NS5B) is an RNA-dependent RNA polymerase (RdRp) that serves as the catalytic core for the replication of the viral RNA genome (UniProt: P26663). Host inosine-5'-monophosphate dehydrogenase (IMPDH) is the rate-limiting enzyme in the de novo biosynthesis of guanine nucleotides, converting inosine monophosphate to xanthosine monophosphate (UniProt: P12268). The simultaneous targeting of these two proteins is a well-established therapeutic strategy for treating chronic Hepatitis C, primarily through the use of Ribavirin. Ribavirin acts as a prodrug that, once phosphorylated, inhibits host IMPDH to deplete intracellular GTP pools and directly interferes with NS5B-mediated RNA synthesis as a mutagen or chain terminator (PubMed: 16435105). This dual mechanism effectively suppresses viral load by inducing error catastrophe in the viral population and limiting the raw materials needed for replication. While highly effective in combination therapies, targeting host IMPDH can lead to systemic toxicities, most notably hemolytic anemia, due to the depletion of ATP and GTP in erythrocytes (StatPearls: NBK513281). Modern treatment regimens often combine NS5B-specific inhibitors with other direct-acting antivirals to maximize efficacy and minimize host-related side effects.

Other names

HCV NS5B RNA-dependent RNA polymerase & host IMPDHNS5B RNA-dependent RNA polymeraseIMPDHInosine monophosphate dehydrogenaseHCV RdRpIMP dehydrogenaseHCV NS5BHost IMPDH

Inhibition of viral RNA-dependent RNA polymerase activity and depletion of intracellular GTP pools through inhibition of host inosine-5'-monophosphate dehydrogenase (PubMed: 16435105).