title: Broad-spectrum antiviral activity of the IMP dehydrogenase inhibitor VX-497: a comparison with ribavirin and demonstration of antiviral additivity with alpha interferon.
abstract: 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 inhibitors such as ribavirin or uncompetitive inhibitors such as mycophenolic acid (MPA) is a depletion of the intracellular GTP and dGTP pools. Ribavirin is approved as an inhaled antiviral agent for treatment of respiratory syncytial virus (RSV) infection and orally, in combination with alpha interferon (IFN-alpha), for the treatment of chronic hepatitis C virus (HCV) infection. VX-497 is a potent, reversible uncompetitive IMPDH inhibitor which is structurally unrelated to other known IMPDH inhibitors. Studies were performed to compare VX-497 and ribavirin in terms of their cytotoxicities and their efficacies against a variety of viruses. They included DNA viruses (hepatitis B virus [HBV], human cytomegalovirus [HCMV], and herpes simplex virus type 1 [HSV-1]) and RNA viruses (respiratory syncytial virus [RSV], parainfluenza-3 virus, bovine viral diarrhea virus, Venezuelan equine encephalomyelitis virus [VEEV], dengue virus, yellow fever virus, coxsackie B3 virus, encephalomyocarditis virus [EMCV], and influenza A virus). VX-497 was 17- to 186-fold more potent than ribavirin against HBV, HCMV, RSV, HSV-1, parainfluenza-3 virus, EMCV, and VEEV infections in cultured cells. The therapeutic index of VX-497 was significantly better than that of ribavirin for HBV and 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 demonstrated additivity when coapplied with IFN-alpha, with VX-497 again being the more potent in this combination. These data are supportive of the hypothesis that VX-497, like ribavirin, is a broad-spectrum antiviral agent.
authors.affiliation: Vertex Pharmaceuticals Inc., Cambridge, Massachusetts 02139-4242, USA. Markland@vpharm.com
authors.forename: W
authors.initials: W
authors.lastname: Markland
authors.forename: T J
authors.initials: TJ
authors.lastname: McQuaid
authors.forename: J
authors.initials: J
authors.lastname: Jain
authors.forename: A D
authors.initials: AD
authors.lastname: Kwong
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002219:Carbamates / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002417:Cattle; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004586:Electrophoresis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts; D006151:Guanosine / Q000494:pharmacology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D016898:Interferon-alpha / Q000494:pharmacology*; D051379:Mice; D008970:Molecular Weight; D010671:Phenylurea Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012254:Ribavirin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects; D014780:Viruses / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D004791:Enzyme Inhibitors; D016898:Interferon-alpha; C407002:N-3-(3-(3-methoxy-4-oxazol-5-ylphenyl)ureido)benzylcarbamic acid tetrahydrofuran-3-yl ester; D010671:Phenylurea Compounds; D006151:Guanosine; D012254:Ribavirin; D007168:IMP Dehydrogenase