Identification and characterization of inhibitors of West Nile virus

Francesc Puig-Basagoiti, Min Qing, Hongping Dong, Bo Zhang, Gang Zou, Zhiming Yuan, Pei Yong Shi

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Although flaviviruses cause significant human diseases, no antiviral therapy is currently available for clinical treatment of these pathogens. To identify flavivirus inhibitors, we performed a high-throughput screening of compound libraries using cells containing luciferase-reporting replicon of West Nile viruses (WNV). Five novel small molecular inhibitors of WNV were identified from libraries containing 96,958 compounds. The inhibitors suppress epidemic strain of WNV in cell culture, with EC50 (50% effective concentration) values of <10 μM and TI (therapeutic index) values of >10. Viral titer reduction assays, using various flaviviruses and nonflaviviruses, showed that the compounds have distinct antiviral spectra. Mode-of-action analysis showed that the inhibitors block distinct steps of WNV replication: four compounds inhibit viral RNA syntheses, while the other compound suppresses both viral translation and RNA syntheses. Biochemical enzyme assays showed that two compounds selectively inhibit viral RNA-dependent RNA polymerase (RdRp), while another compound specifically inhibits both RdRp and methyltransferase. The identified compounds could potentially be developed for treatment of flavivirus infections.

Original languageEnglish (US)
Pages (from-to)71-79
Number of pages9
JournalAntiviral research
Volume83
Issue number1
DOIs
StatePublished - Jul 1 2009
Externally publishedYes

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Keywords

  • Antiviral drug discovery
  • Flavivirus replication
  • High-throughput screening
  • RNA cap methyltransferase
  • RNA-dependent RNA polymerase
  • West Nile virus

ASJC Scopus subject areas

  • Pharmacology
  • Virology

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