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dc.contributor.authorWang, Qing-Yinen
dc.contributor.authorDong, Hongpingen
dc.contributor.authorZou, Binen
dc.contributor.authorKaruna, Ratnaen
dc.contributor.authorWan, Kah Feien
dc.contributor.authorZou, Jingen
dc.contributor.authorSusila, Agathaen
dc.contributor.authorYip, Andyen
dc.contributor.authorShan, Chaoen
dc.contributor.authorYeo, Kim Longen
dc.contributor.authorXu, Haoyingen
dc.contributor.authorDing, Meien
dc.contributor.authorChan, Wai Lingen
dc.contributor.authorGu, Fengen
dc.contributor.authorSeah, Peck Geeen
dc.contributor.authorLiu, Weien
dc.contributor.authorLakshminarayana, Suresh B.en
dc.contributor.authorKang, CongBaoen
dc.contributor.authorLescar, Julienen
dc.contributor.authorBlasco, Francescaen
dc.contributor.authorSmith, Paul W.en
dc.contributor.authorShi, Pei-Yongen
dc.contributor.editorDiamond, M. S.en
dc.identifier.citationWang, Q.-Y., Dong, H., Zou, B., Karuna, R., Wan, K. F., Zou, J., et al. (2015). Discovery of Dengue Virus NS4B Inhibitors. Journal of Virology, 89(16), 8233-8244.en
dc.description.abstractThe four serotypes of dengue virus (DENV-1 to -4) represent the most prevalent mosquito-borne viral pathogens in humans. No clinically approved vaccine or antiviral is currently available for DENV. Here we report a spiropyrazolopyridone compound that potently inhibits DENV both in vitro and in vivo. The inhibitor was identified through screening of a 1.8-million-compound library by using a DENV-2 replicon assay. The compound selectively inhibits DENV-2 and -3 (50% effective concentration [EC50], 10 to 80 nM) but not DENV-1 and -4 (EC50, >20 μM). Resistance analysis showed that a mutation at amino acid 63 of DENV-2 NS4B (a nonenzymatic transmembrane protein and a component of the viral replication complex) could confer resistance to compound inhibition. Genetic studies demonstrate that variations at amino acid 63 of viral NS4B are responsible for the selective inhibition of DENV-2 and -3. Medicinal chemistry improved the physicochemical properties of the initial “hit” (compound 1), leading to compound 14a, which has good in vivo pharmacokinetics. Treatment of DENV-2-infected AG129 mice with compound 14a suppressed viremia, even when the treatment started after viral infection. The results have proven the concept that inhibitors of NS4B could potentially be developed for clinical treatment of DENV infection. Compound 14a represents a potential preclinical candidate for treatment of DENV-2- and -3-infected patients.en
dc.relation.ispartofseriesJournal of Virologyen
dc.rights© 2015 American Society for Microbiology. This paper was published in Journal of Virology and is made available as an electronic reprint (preprint) with permission of American Society for Microbiology. The published version is available at: []. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law.en
dc.titleDiscovery of Dengue Virus NS4B Inhibitorsen
dc.typeJournal Articleen
dc.contributor.schoolSchool of Biological Sciencesen
dc.description.versionPublished versionen
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