Discovery of small molecule inhibitors of West Nile virus using a high-throughput sub-genomic replicon screen

Baohua Gu, Serguey Ouzunov, Liguan Wang, Peter Mason, Nigel Bourne, Andy Cuconati, Timothy M. Block

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

West Nile virus (WNV) is a positive-sense, single-stranded RNA virus of the family Flaviviridae. WNV persistently infects insect cells, but can causes acute cytopathic infection of mammalian cells and is an etiologic agent of viral encephalitis in humans. By using a cell line expressing a WNV subgenomic replicon [Rossi, S.L., Zhao, Q., O'Donnell, V.K., Mason, P.W., 2005. Adaptation of West Nile virus replicons to cells in culture and use of replicon-bearing cells to probe antiviral action. Virology 331 (2), 457-470], we developed a high-throughput assay and used it to screen a library of small molecule compounds for inhibitors of WNV replication in the absence of live virus. Here we report the identification of novel small molecule inhibitors for WNV replicon replication. We demonstrate that the compounds inhibited WNV replication-dependent luciferase expression in the replicon cells and reduced WNV viral protein accumulation and viral RNA copy number in the replicon cells. Two classes of compounds with multiple hits, parazolotrahydrothophenes and pyrozolopyrimidines, showed preliminary structure-activity relationships. In WNV infection assays, one pyrozolopyrimidine compound was confirmed to have antiviral activity. These compounds should be valuable for developing anti-WNV therapeutic drugs as well as research tools to study the mechanism of WNV replication.

Original languageEnglish (US)
Pages (from-to)39-50
Number of pages12
JournalAntiviral Research
Volume70
Issue number2
DOIs
StatePublished - Jun 2006

Fingerprint

West Nile virus
Replicon
Virus Replication
Antiviral Agents
Flaviviridae
Viral Encephalitis
Small Molecule Libraries
Virology
RNA Viruses
Viral RNA
Viral Proteins
Virus Diseases
Structure-Activity Relationship
Luciferases
Insects
Cell Culture Techniques

Keywords

  • High-throughput screen (HTS)
  • Small molecule inhibitor
  • West Nile virus

ASJC Scopus subject areas

  • Virology
  • Pharmacology

Cite this

Discovery of small molecule inhibitors of West Nile virus using a high-throughput sub-genomic replicon screen. / Gu, Baohua; Ouzunov, Serguey; Wang, Liguan; Mason, Peter; Bourne, Nigel; Cuconati, Andy; Block, Timothy M.

In: Antiviral Research, Vol. 70, No. 2, 06.2006, p. 39-50.

Research output: Contribution to journalArticle

Gu, Baohua ; Ouzunov, Serguey ; Wang, Liguan ; Mason, Peter ; Bourne, Nigel ; Cuconati, Andy ; Block, Timothy M. / Discovery of small molecule inhibitors of West Nile virus using a high-throughput sub-genomic replicon screen. In: Antiviral Research. 2006 ; Vol. 70, No. 2. pp. 39-50.
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