Flaviviruses are sensitive to inhibition of thymidine synthesis pathways

Matthew A. Fischer, Jessica L. Smith, David Shum, David A. Stein, Christopher Parkins, Bhavneet Bhinder, Constantin Radu, Alec J. Hirsch, Hakim Djaballah, Jay A. Nelson, Klaus Früh

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Dengue virus has emerged as a global health threat to over one-third of humankind. As a positive-strandRNAvirus, dengue virus relies on the host cell metabolism for its translation, replication, and egress. Therefore, a better understanding of the host cell metabolic pathways required for dengue virus infection offers the opportunity to develop new approaches for therapeutic intervention. In a recently described screen of known drugs and bioactive molecules, we observed that methotrexate and floxuridine inhibited dengue virus infections at low micromolar concentrations. Here, we demonstrate that all serotypes of dengue virus, as well as West Nile virus, are highly sensitive to both methotrexate andfloxuridine, whereas otherRNAviruses (Sindbis virus and vesicular stomatitis virus) are not. Interestingly, flavivirus replication was restored by folinic acid, a thymidine precursor, in the presence of methotrexate and by thymidine in the presence of floxuridine, suggesting an unexpected role for thymidine in flavivirus replication. Since thymidine is not incorporated intoRNAgenomes, it is likely that increased thymidine production is indirectly involved in flavivirus replication. A possible mechanism is suggested by the finding that p53 inhibition restored dengue virus replication in the presence of floxuridine, consistent with thymidine-less stress triggering p53-mediated antiflavivirus effects in infected cells. Our data reveal thymidine synthesis pathways as new and unexpected therapeutic targets for antiflaviviral drug development.

Original languageEnglish (US)
Pages (from-to)9411-9419
Number of pages9
JournalJournal of virology
Volume87
Issue number17
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Fischer, M. A., Smith, J. L., Shum, D., Stein, D. A., Parkins, C., Bhinder, B., Radu, C., Hirsch, A. J., Djaballah, H., Nelson, J. A., & Früh, K. (2013). Flaviviruses are sensitive to inhibition of thymidine synthesis pathways. Journal of virology, 87(17), 9411-9419. https://doi.org/10.1128/JVI.00101-13