Discovery of Dengue Virus NS4B Inhibitors

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....

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Main 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
Other Authors: Diamond, M. S.
Format: Article
Language:English
Published: 2015
Online Access:https://hdl.handle.net/10356/103770
http://hdl.handle.net/10220/38794
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.10356-1037702023-02-28T17:02:31Z Discovery of Dengue Virus NS4B Inhibitors 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 Diamond, M. S. School of Biological Sciences 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. Published version 2015-10-13T02:49:03Z 2019-12-06T21:19:52Z 2015-10-13T02:49:03Z 2019-12-06T21:19:52Z 2015 2015 Journal Article 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. https://hdl.handle.net/10356/103770 http://hdl.handle.net/10220/38794 10.1128/JVI.00855-15 26018165 en Journal of Virology © 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: [http://dx.doi.org/10.1128/JVI.00855-15]. 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. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
description 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.
author2 Diamond, M. S.
author_facet Diamond, M. S.
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
format Article
author 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
spellingShingle 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
Discovery of Dengue Virus NS4B Inhibitors
author_sort Wang, Qing-Yin
title Discovery of Dengue Virus NS4B Inhibitors
title_short Discovery of Dengue Virus NS4B Inhibitors
title_full Discovery of Dengue Virus NS4B Inhibitors
title_fullStr Discovery of Dengue Virus NS4B Inhibitors
title_full_unstemmed Discovery of Dengue Virus NS4B Inhibitors
title_sort discovery of dengue virus ns4b inhibitors
publishDate 2015
url https://hdl.handle.net/10356/103770
http://hdl.handle.net/10220/38794
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