Inhibition of dengue virus through suppression of host pyrimidine biosynthesis

Qing Yin Wang, Simon Bushell, Min Qing, Hao Ying Xu, Aurelio Bonavia, Sandra Nunes, Jing Zhou, Mee Kian Poh, Paola Florez de Sessions, Pornwaratt Niyomrattanakit, Hongping Dong, Keith Hoffmaster, Anne Goh, Shahul Nilar, Wouter Schul, Susan Jones, Laura Kramer, Teresa Compton, Pei Yong Shi

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

Viral replication relies on the host to supply nucleosides. Host enzymes involved in nucleoside biosynthesis are potential targets for antiviral development. Ribavirin (a known antiviral drug) is such an inhibitor that suppresses guanine biosynthesis; depletion of the intracellular GTP pool was shown to be the major mechanism to inhibit flavivirus. Along similar lines, inhibitors of the pyrimidine biosynthesis pathway could be targeted for potential antiviral development. Here we report on a novel antiviral compound (NITD-982) that inhibits host dihydroorotate dehydrogenase (DHODH), an enzyme required for pyrimidine biosynthesis. The inhibitor was identified through screening 1.8 million compounds using a dengue virus (DENV) infection assay. The compound contains an isoxazole-pyrazole core structure, and it inhibited DENV with a 50% effective concentration (EC50) of 2.4 nM and a 50% cytotoxic concentration (CC50) of >5 μM. NITD-982 has a broad antiviral spectrum, inhibiting both flaviviruses and nonflaviviruses with nanomolar EC90s. We also show that (i) the compound inhibited the enzymatic activity of recombinant DHODH, (ii) an NITD-982 analogue directly bound to the DHODH protein, (iii) supplementing the culture medium with uridine reversed the compoundmediated antiviral activity, and (iv) DENV type 2 (DENV-2) variants resistant to brequinar (a known DHODH inhibitor) were cross resistant to NITD-982. Collectively, the results demonstrate that the compound inhibits DENV through depleting the intracellular pyrimidine pool. In contrast to the in vitro potency, the compound did not show any efficacy in the DENV-AG129 mouse model. The lack of in vivo efficacy is likely due to the exogenous uptake of pyrimidine from the diet or to a high plasma protein-binding activity of the current compound.

Original languageEnglish (US)
Pages (from-to)6548-6556
Number of pages9
JournalJournal of virology
Volume85
Issue number13
DOIs
StatePublished - Jul 1 2011
Externally publishedYes

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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  • Cite this

    Wang, Q. Y., Bushell, S., Qing, M., Xu, H. Y., Bonavia, A., Nunes, S., Zhou, J., Poh, M. K., de Sessions, P. F., Niyomrattanakit, P., Dong, H., Hoffmaster, K., Goh, A., Nilar, S., Schul, W., Jones, S., Kramer, L., Compton, T., & Shi, P. Y. (2011). Inhibition of dengue virus through suppression of host pyrimidine biosynthesis. Journal of virology, 85(13), 6548-6556. https://doi.org/10.1128/JVI.02510-10