Broad-spectrum antiviral activity of the IMP dehydrogenase inhibitor VX-497: a comparison with ribavirin and demonstration of antiviral additivity with alpha interferon

The enzyme IMP dehydrogenase (IMPDH) catalyzes an essential step in the de novo biosynthesis of guanine nucleotides, namely, the conversion of IMP to XMP. The major event occurring in cells exposed to competitive IMPDH inhibi tors such as ribavirin or uncompetitive inhibitors such as mycophenolic aci d (MPA) is a depletion of the intracellular GTP and dGTP pools. Ribavirin i s approved as an inhaled antiviral agent for treatment of respiratory syncy tial virus (RSV) infection and orally, in combination with alpha interferon (IFN-alpha), for the treatment of chronic hepatitis C virus (HCV) infectio n. VX-497 is a potent, reversible uncompetitive IMPDH inhibitor which is st ructurally unrelated to other known IMPDH inhibitors. Studies were performe d to compare VX-497 and ribavirin in terms of their cytotoxicities and thei r efficacies against a variety of viruses. They included DNA viruses (hepat itis B virus [HBV], human cytomegalovirus [HCMV], and herpes simplex virus type 1 [HSV-1]) and RNA viruses (respiratory syncytial virus [RSV], parainf luenza-3 virus, bovine viral diarrhea virus, Venezuelan equine encephalomye litis virus [VEEV], dengue virus, yellow fever virus, coxsackie B3 virus, e ncephalomyocarditis virus [EMCV], and influenza A virus). VX-497 aas 17-to 186-fold more potent than ribavirin against HBV, HCMV, RSV, HSV-I, parainfl uenza-3 virus, EMCV, and VEEV infections in cultured cells. The therapeutic index of VX-497 was significantly better than that of ribavirin for HBV an d HCMV (14- and 39-fold, respectively). Finally, the antiviral effect of VX -497 in combination with IFN-alpha. was compared to that of ribavirin with IFN-alpha in the EMCV replication system. Both VX-497 and ribavirin demonst rated additivity when coapplied with IFN-alpha, with VX-497 again being the more potent in this combination. These data are supportive of the hypothes is that VX-497, like ribavirin, is a broad-spectrum antiviral agent.