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Comparative Study
. 2000 Apr;44(4):859-66.
doi: 10.1128/AAC.44.4.859-866.2000.

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

W Markland  1 , T J McQuaid, J Jain, A D Kwong
Affiliations
Comparative Study

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

W Markland et al. Antimicrob Agents Chemother. 2000 Apr.

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.

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Figures

FIG. 1
FIG. 1
Chemical structure of VX-497.
FIG. 2
FIG. 2
(a) Effect of ribavirin on viability of HepG2 2.2.15 cells and HBV replication. (b) Effect of VX-497 on viability of HepG2 2.2.15 cells and HBV replication. (c) Effect of ribavirin on viability of Vero cells and HSV-1 replication. (d) Effect of VX-497 on viability of Vero cells and HSV-1 replication. Cell viability (striped bars) is measured (in percent) relative to cell growth in the absence of drug. Antiviral activity (solid bars) is measured (in percent) relative to viral replication in the absence of drug. Results are the means of triplicate determinations, with standard deviations shown.
FIG. 3
FIG. 3
Effects of IFN-α (units per 100-μl well) (a), ribavirin (b), and VX-497 (c) on the viability of L929 cells and EMCV replication. Cell viability (striped bars) is measured (in percent) relative to cell growth in the absence of drug. Viral yield (solid bars) is measured (in percent) relative to viral replication in the absence of drug. Results are the means of triplicate determinations, with standard deviations shown.
FIG. 4
FIG. 4
Effects of the combination of ribavirin and IFN-α (a) or of VX-497 and IFN-α on the yield of EMCV in L929 cells. Viral yield is measured (in percent) relative to viral replication in the absence of either drug. Results are the means of triplicate determinations. (Standard deviations were on average 10% of the mean, with a range no more than 20% of the mean.) IFNa, IFN-α.
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References

    1. Allison A C, Hovi T, Watts R W E, Webster A D B. The role of de novo purine synthesis in lymphocyte transformation. Ciba Found Symp. 1977;48:207–224. - PubMed
    1. Cassidy L F, Patterson J L. Mechanism of La Crosse virus inhibition by ribavirin. Antimicrob Agents Chemother. 1989;33:2009–2011. - PMC - PubMed
    1. Colby T D, Vanderveen K, Strickler M D, Markham G D, Goldstein B M. Crystal structure of human type II inosine monophosphate dehydrogenase: implications for ligand binding and drug design. Proc Natl Acad Sci USA. 1999;96:3531–3536. - PMC - PubMed
    1. De Clercq E. Antiviral agents: characteristic activity spectrum depending on the molecular target with which they interact. New York, N.Y: Academic Press, Inc.; 1993. pp. 1–55. - PubMed
    1. De Clercq E. Trends in the development of new antiviral agents for the chemotherapy of infections caused by herpes viruses and retroviruses. Rev Med Virol. 1995;5:149–164.

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