Viral RNA-dependent RNA polymerase (RdRp) and host inosine monophosphate dehydrogenase (IMPDH) (RdRp and IMPDH)

Viral RNA-dependent RNA polymerase (RdRp) is an essential enzyme for the replication and transcription of RNA viruses, such as Hepatitis C and Influenza (UniProt P26663). Because RdRp lacks a functional homolog in human cells, it is a primary target for direct-acting antiviral drugs that act as chain terminators or mutagens (PubMed 11113130). Host inosine monophosphate dehydrogenase (IMPDH) is the rate-limiting enzyme in the de novo biosynthesis of guanine nucleotides, converting inosine monophosphate to xanthosine monophosphate (UniProt P12268). Inhibition of IMPDH leads to the depletion of intracellular GTP pools, which indirectly hinders viral RNA synthesis by limiting available substrates (PubMed 16433621). The combination of these two targets is classically associated with the mechanism of ribavirin, a broad-spectrum antiviral agent (PubChem CID 37542). By simultaneously inhibiting RdRp and depleting GTP through IMPDH inhibition, these drugs exert a synergistic effect that suppresses viral load and induces error-prone replication. This dual-target approach is particularly effective against a wide range of RNA viruses but is associated with significant side effects like hemolytic anemia (StatPearls NBK513243).

Other names

RNA-directed RNA polymeraseInosine-5'-monophosphate dehydrogenaseRdRpIMPDHIMPDH1IMPDH2

Direct inhibition of viral RNA synthesis via RdRp and indirect suppression of replication through the depletion of intracellular guanosine triphosphate (GTP) pools via IMPDH inhibition (PubMed 11113130, PubMed 16433621).