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Title: Discovery of Dengue Virus NS4B Inhibitors
Authors: Wang, Qing-Yin
Dong, Hongping
Zou, Bin
Karuna, Ratna
Wan, Kah Fei
Zou, Jing
Susila, Agatha
Yip, Andy
Shan, Chao
Yeo, Kim Long
Xu, Haoying
Ding, Mei
Chan, Wai Ling
Gu, Feng
Seah, Peck Gee
Liu, Wei
Lakshminarayana, Suresh B.
Kang, CongBao
Lescar, Julien
Blasco, Francesca
Smith, Paul W.
Shi, Pei-Yong
Issue Date: 2015
Source: Wang, 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.
Series/Report no.: Journal of Virology
Abstract: The 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.
DOI: 10.1128/JVI.00855-15
Schools: School of Biological Sciences 
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.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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