1887

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Volume 87, Issue 7

Inhibition of dengue virus replication by mycophenolic acid and ribavirin Free

Abstract

Dengue viruses (DEN), mosquito-borne members of the family , are human pathogens of global significance. The effects of mycophenolic acid (MPA) and ribavirin (RBV) on DEN replication in monkey kidney (LLC-MK2) cells were examined. MPA (IC=0.4±0.3 μM) and RBV (IC=50.9±18 μM) inhibited DEN2 replication. Quantitative real-time RT-PCR of viral RNA and plaque assays of virions from DEN2-infected and MPA (10 μM)- and RBV (⩾200 μM)-treated cells showed a fivefold increase in defective viral RNA production by cells treated with each drug. Moreover, a dramatic reduction of intracellular viral replicase activity was seen by replicase assays. Guanosine reversed the inhibition of these compounds, suggesting that one mode of antiviral action of MPA and RBV is by inhibition of inosine monophosphate dehydrogenase and thereby depletion of the intracellular GTP pool. In addition, RBV may act by competing with guanine-nucleotide precursors in viral RNA translation, replication and 5′ capping.

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2006-07-01
2024-04-19
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References

  1. Ackermann M., Padmanabhan R. 2001; De novo synthesis of RNA by the dengue virus RNA-dependent RNA polymerase exhibits temperature dependence at the initiation but not elongation phase. J Biol Chem 276:39926–39937 [CrossRef]
     [Google Scholar]
  2. Allison A. C., Eugui E. M. 2000; Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 47:85–118 [CrossRef]
     [Google Scholar]
  3. Barrett A. D. T. 2001; Current status of flavivirus vaccines. Ann N Y Acad Sci 951:262–271
     [Google Scholar]
  4. Benarroch D., Egloff M.-P., Mulard L., Guerreiro C., Romette J.-L., Canard B. 2004; A structural basis for the inhibition of the NS5 dengue virus mRNA 2′- O -methyltransferase domain by ribavirin 5′-triphosphate. J Biol Chem 279:35638–35643 [CrossRef]
     [Google Scholar]
  5. Bullingham R., Monroe S., Nicholls A., Hale M. 1996; Pharmacokinetics and bioavailability of mycophenolate mofetil in healthy subjects after single-dose oral and intravenous administration. J Clin Pharmacol 36:315–324 [CrossRef]
     [Google Scholar]
  6. Charnsilpa W., Takhampunya R., Endy T. P., Mammen M. P. Jr, Libraty D. H., Ubol S. 2005; Nitric oxide radical suppresses replication of wild-type dengue 2 viruses in vitro. J Med Virol 77:89–95 [CrossRef]
     [Google Scholar]
  7. Chou T.-C., Talaly P. 1977; A simple generalized equation for the analysis of multiple inhibitions of Michaelis-Menten kinetic systems. J Biol Chem 252:6438–6442
     [Google Scholar]
  8. Chou T.-C., Motzer R. J., Tong Y., Bosl G. J. 1994; Computerized quantitation of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: a rational approach to clinical protocol design. J Natl Cancer Inst 86:1517–1524 [CrossRef]
     [Google Scholar]
  9. Chu P. W. G., Westaway E. G. 1985; Replication strategy of Kunjin virus: evidence for recycling role of replicative form RNA as template in semiconservative and asymmetric replication. Virology 140:68–79 [CrossRef]
     [Google Scholar]
  10. Chu P. W. G., Westaway E. G. 1987; Characterization of Kunjin virus RNA-dependent RNA polymerase: reinitiation of synthesis in vitro . Virology 157:330–337 [CrossRef]
     [Google Scholar]
  11. Crotty S., Maag D., Arnold J. J., Zhong W., Lau J. Y. N., Hong Z., Andino R., Cameron C. E. 2000; The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nat Med 6:1375–1379 [CrossRef]
     [Google Scholar]
  12. Crotty S., Cameron C. E., Andino R. 2001; RNA virus error catastrophe: direct molecular test by using ribavirin. Proc Natl Acad Sci U S A 98:6895–6900 [CrossRef]
     [Google Scholar]
  13. Day C. W., Smee D. F., Julander J. G., Yamshchikov V. F., Sidwell R. W., Morrey J. D. 2005; Error-prone replication of West Nile virus caused by ribavirin. Antiviral Res 67:38–45 [CrossRef]
     [Google Scholar]
  14. Diamond M. S., Zachariah M., Harris E. 2002; Mycophenolic acid inhibits dengue virus infection by preventing replication of viral RNA. Virology 304:211–221 [CrossRef]
     [Google Scholar]
  15. Dulbecco R., Vogt M. 1954; One-step growth curve of Western equine encephalomyelitis virus on chicken embryo cells grown in vitro and analysis of virus yields from single cells. J Exp Med 99:183–199 [CrossRef]
     [Google Scholar]
  16. Egloff M.-P., Benarroch D., Selisko B., Romette J.-L., Canard B. 2002; An RNA cap (nucleoside-2′- O -)-methyltransferase in the flavivirus RNA polymerase NS5: crystal structure and functional characterization. EMBO J 21:2757–2768 [CrossRef]
     [Google Scholar]
  17. Graci J. D., Cameron C. E. 2002; Quasispecies, error catastrophe, and the antiviral activity of ribavirin. Virology 298:175–180 [CrossRef]
     [Google Scholar]
  18. Grun J. B., Brinton M. A. 1986; Characterization of West Nile virus RNA-dependent RNA polymerase and cellular terminal adenylyl and uridylyl transferases in cell-free extracts. J Virol 60:1113–1124
     [Google Scholar]
  19. Gubler D. J. 1998; Dengue and dengue hemorrhagic fever. Clin Microbiol Rev 11:480–496
     [Google Scholar]
  20. Guyatt K. J., Westaway E. G., Khromykh A. A. 2001; Expression and purification of enzymatically active recombinant RNA-dependent RNA polymerase (NS5) of the flavivirus Kunjin. J Virol Methods 92:37–44 [CrossRef]
     [Google Scholar]
  21. Halstead S. B., Deen J. 2002; The future of dengue vaccines. Lancet 360:1243–1245 [CrossRef]
     [Google Scholar]
  22. Helt A.-M., Harris E. 2005; S-phase-dependent enhancement of dengue virus 2 replication in mosquito cells, but not in human cells. J Virol 79:13218–13230 [CrossRef]
     [Google Scholar]
  23. Houng H.-S. H., Hritz D., Kanesa-Thasan N. 2000; Quantitative detection of dengue 2 virus using fluorogenic RT-PCR based on 3′-noncoding sequence. J Virol Methods 86:1–11 [CrossRef]
     [Google Scholar]
  24. Irie K., Mohan P. M., Sasaguri Y., Putnak R., Padmanabhan R. 1989; Sequence analysis of cloned dengue virus type 2 genome (New Guinea-C strain). Gene 75:197–211 [CrossRef]
     [Google Scholar]
  25. Leyssen P., Van Lommel A., Drosten C., Schmitz H., De Clercq E., Neyts J. 2001; A novel model for the study of the therapy of flavivirus infections using the Modoc virus. Virology 279:27–37 [CrossRef]
     [Google Scholar]
  26. Leyssen P., Balzarini J., De Clercq E., Neyts J. 2005; The predominant mechanism by which ribavirin exerts its antiviral activity in vitro against flaviviruses and paramyxoviruses is mediated by inhibition of IMP dehydrogenase. J Virol 79:1943–1947 [CrossRef]
     [Google Scholar]
  27. Lo M. K., Tilgner M., Shi P.-Y. 2003; Potential high-throughput assay for screening inhibitors of West Nile virus replication. J Virol 77:12901–12906 [CrossRef]
     [Google Scholar]
  28. Maag D., Castro C., Hong Z., Cameron C. E. 2001; Hepatitis C virus RNA-dependent RNA polymerase (NS5B) as a mediator of the antiviral activity of ribavirin. J Biol Chem 276:46094–46098 [CrossRef]
     [Google Scholar]
  29. Markland W., McQuaid T. J., Jain J., Kwong A. D. 2000; Broad-spectrum antiviral activity of the IMP dehydrogenase inhibitor VX-497: a comparison with ribavirin and demonstration of antiviral additivity with alpha interferon. Antimicrob Agents Chemother 44:859–866 [CrossRef]
     [Google Scholar]
  30. Morrey J. D., Smee D. F., Sidwell R. W., Tseng C. 2002; Identification of active antiviral compounds against a New York isolate of West Nile virus. Antiviral Res 55:107–116 [CrossRef]
     [Google Scholar]
  31. Muller W. E., Maidhof A., Taschner H., Zahn R. K. 1977; Virazole (1- β -d-ribofuranosyl-1,2,4-triazole-3-carboxamide): a cytostatic agent. Biochem Pharmacol 26:1071–1075 [CrossRef]
     [Google Scholar]
  32. Smee D. F., Bray M., Huggins J. W. 2001; Antiviral activity and mode of action studies of ribavirin and mycophenolic acid against orthopoxviruses in vitro. Antivir Chem Chemother 12:327–335 [CrossRef]
     [Google Scholar]
  33. Streeter D. G., Witkowski J. T., Khare G. P., Sidwell R. W., Bauer R. J., Robins R. K., Simon L. N. 1973; Mechanism of action of 1- β -d-ribofuranosyl-1,2,4-triazole-3-carboxamide (Virazole), a new broad-spectrum antiviral agent. Proc Natl Acad Sci U S A 70:1174–1178 [CrossRef]
     [Google Scholar]
  34. Tan B.-H., Fu J., Sugrue R. J., Yap E.-H., Chan Y.-C., Tan Y. H. 1996; Recombinant dengue type 1 virus NS5 protein expressed in Escherichia coli exhibits RNA-dependent RNA polymerase activity. Virology 216:317–325 [CrossRef]
     [Google Scholar]
  35. Uchil P. D., Satchidanandam V. 2003; Characterization of RNA synthesis, replication mechanism, and in vitro RNA-dependent RNA polymerase activity of Japanese encephalitis virus. Virology 307:358–371 [CrossRef]
     [Google Scholar]
  36. Westaway E. G., Mackenzie J. M., Khromykh A. A. 2002; Replication and gene function in Kunjin virus. Curr Top Microbiol Immunol 267:323–351
     [Google Scholar]
  37. Westaway E. G., Mackenzie J. M., Khromykh A. A. 2003; Kunjin RNA replication and applications of Kunjin replicons. Adv Virus Res 59:99–140
     [Google Scholar]
  38. You S., Padmanabhan R. 1999; A novel in vitro replication system for Dengue virus: initiation of RNA synthesis at the 3′-end of exogenous viral RNA templates requires 5′- and 3′-terminal complementary sequence motifs of the viral RNA. J Biol Chem 274:33714–33722 [CrossRef]
     [Google Scholar]
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Inhibition of dengue virus replication by mycophenolic acid and ribavirin
J. Gen. Virol. 87, 1947 (2006); https://doi.org/10.1099/vir.0.81655-0
/content/journal/jgv/10.1099/vir.0.81655-0
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