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Antimicrobial Agents and Chemotherapy, April 2006, p. 1320-1329, Vol. 50, No. 4
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.4.1320-1329.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Triaryl Pyrazoline Compound Inhibits Flavivirus RNA Replication

Francesc Puig-Basagoiti,1 Mark Tilgner,1 Brett M. Forshey,1 Sean M. Philpott,1,2 Noel G. Espina,1 David E. Wentworth,1,2 Scott J. Goebel,1 Paul S. Masters,1,2 Barry Falgout,3 Ping Ren,1 David M. Ferguson,4* and Pei-Yong Shi1,2*

Wadsworth Center, New York State Department of Health,1 Department of Biomedical Sciences, University at Albany, State University of New York, Albany, New York 12208,2 U.S. Food and Drug Administration, Bethesda, Maryland 20892,3 Department of Medicinal Chemistry and Center for Drug Design, University of Minnesota, Minneapolis, Minnesota 554554

Received 10 November 2005/ Returned for modification 19 January 2006/ Accepted 24 January 2006

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 µM and a compound concentration of ≥300 µM 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.

* Corresponding author. Mailing address for Pei-Yong Shi: 120 New Scotland Avenue, Wadsworth Center, New York State Department of Health, Albany, NY 12208. Phone: (518) 473-7487. Fax: (518) 473-1326. E-mail: ship{at}wadsworth.org. Mailing address for David M. Ferguson: Department of Medicinal Chemistry and Center for Drug Design, University of Minnesota, Minneapolis, MN 55455. Phone: (612) 626-2601. Fax: (612) 624-0139. E-mail: ferguson{at}umn.edu.

Antimicrobial Agents and Chemotherapy, April 2006, p. 1320-1329, Vol. 50, No. 4
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.4.1320-1329.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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