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Antimicrob Agents Chemother 2006 Apr;50(4):1320-9

Triaryl pyrazoline compound inhibits flavivirus RNA replication.

Puig-Basagoiti F, Tilgner M, Forshey BM, Philpott SM, Espina NG, Wentworth DE, Goebel SJ, Masters PS, Falgout B, Ren P, Ferguson DM, Shi PY

Ferguson DM, New York State Dept Hlth, Wadsworth Ctr Labs & Res, 120 New Scotland Ave, Albany, NY 12208 USA New York State Dept Hlth, Wadsworth Ctr Labs & Res, Albany, NY 12208 USA SUNY Albany, Dept Biomed Sci, Albany, NY 12208 USA US FDA, Bethesda, MD 20892 USA Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA Univ Minnesota, Ctr Drug Design, Minneapolis, MN 55455 USA

Abstract

Triaryl pyrazoline {[5-(4-chloro-phenyl)-3-thiophen-2-yl-4,5-dihydro-pyrazol-1-yl]-phenyl-methanone} inhibits flavivirus infection in cell culture. The inhibitor was identified through high-throughput screening of a compound library using a luciferase-expressing West Nile (WN) virus infection assay. The compound inhibited an epidemic strain of WN virus without detectable cytotoxicity (a 50% effective concentration of 28 microM and a compound concentration of >or=300 microM required to reduce 50% cell viability). Besides WN virus, the compound also inhibited other flaviviruses (dengue, yellow fever, and St. Louis encephalitis viruses), an alphavirus (Western equine encephalitis virus), a coronavirus (mouse hepatitis virus), and a rhabdovirus (vesicular stomatitis virus). However, the compound did not suppress an orthomyxovirus (influenza virus) or a retrovirus (human immunodeficiency virus type 1). Mode-of-action analyses in WN virus showed that the compound did not inhibit viral entry or virion assembly but specifically suppressed viral RNA synthesis. To examine the mechanism of inhibition of dengue virus, we developed two replicon systems for dengue type 1 virus: (i) a stable cell line that harbored replicons containing a luciferase reporter and a neomycin phosphotransferase selection marker and (ii) a luciferase-expressing replicon that could differentiate between viral translation and RNA replication. Analyses of the compound in the dengue type 1 virus replicon systems showed that it weakly suppressed viral translation but significantly inhibited viral RNA synthesis. Overall, the results demonstrate that triaryl pyrazoline exerts a broad spectrum of antiflavivirus activity through potent inhibition of viral RNA replication. This novel inhibitor could be developed for potential treatment of flavivirus infection.


Category: Journal Article, Peer
PubMed ID: #16569847
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2011-10-04 Entry Last Modified: 2012-08-29
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