Inhibition of inosine monophosphate dehydrogenase (IMPDH) by the antiviral compound, 2-vinylinosine monophosphate.

A new enzyme-mediated synthesis of 2-vinylinosine, a compound with broad-spectrum RNA antiviral activity, is described. In order to understand the mechanism of action of this compound, we synthesized its monophosphate and investigated the behavior of that compound toward the enzyme, inosine monophosphate dehydrogenase (IMPDH), a key enzyme involved in the biosynthesis of nucleotides. 2-Vinylinosine monophosphate is a potent inhibitor of IMPDH with a K(i) of 3.98 microM (k(inact)=2.94 x 10(-2) s(-1)). The antiviral activity of 2-vinylinosine may be explained by its cellular conversion to the monophosphate through the sequential action of PNP and HGPRT and subsequent inhibition of IMPDH by the cellularly produced 2-vinylinosine 5'-monophosphate.