Flaviviruses are sensitive to inhibition of thymidine synthesis pathways Journal Article

Authors: 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.
Article Title: Flaviviruses are sensitive to inhibition of thymidine synthesis pathways
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. © 2013, American Society for Microbiology.
Journal Title: Journal of Virology
Volume: 87
Issue: 17
ISSN: 0022-538X
Publisher: American Society for Microbiology  
Date Published: 2013-09-01
Start Page: 9411
End Page: 9419
Language: English
DOI: 10.1128/jvi.00101-13
PROVIDER: scopus
PMCID: PMC3754125
PUBMED: 23824813
Notes: --- - "Export Date: 1 October 2013" - "CODEN: JOVIA" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Bhavneet Bhinder
    30 Bhinder
  2. Hakim Djaballah
    100 Djaballah
  3. Constantin Radu
    27 Radu
  4. David Shum
    53 Shum