Inosine-5-monophosphate dehydrogenase (IMPDH)

Inosine-5-monophosphate dehydrogenase (IMPDH) is the rate-limiting enzyme in the de novo biosynthesis of guanine nucleotides, catalyzing the NAD+-dependent oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) (UniProt P12268). This enzyme is a critical therapeutic target because many viruses and rapidly proliferating cells, such as activated T-cells, depend on de novo synthesis rather than the salvage pathway to maintain GTP levels (PubMed: 11322733). In the context of viral infection, IMPDH inhibition leads to the depletion of intracellular GTP pools, which directly impairs viral RNA polymerase activity and the formation of the 5-prime cap on viral mRNA (PubMed: 15596431). This disruption effectively halts viral mRNA synthesis and subsequent protein production, limiting viral spread. Clinically, IMPDH is targeted by broad-spectrum antivirals like ribavirin and immunosuppressants like mycophenolate mofetil (StatPearls: NBK559255). However, targeting this central metabolic enzyme can result in significant safety concerns, including dose-limiting anemia and gastrointestinal toxicity.

Other names

IMP dehydrogenaseIMPDInosine-5-prime-monophosphate dehydrogenaseIMPDH1IMPDH2

Inhibition of IMPDH depletes intracellular GTP and dGTP pools, which are essential substrates for viral RNA-dependent RNA polymerase and the mRNA capping machinery, thereby halting viral mRNA synthesis and replication.