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....
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2015
|
| Online Access: | https://hdl.handle.net/10356/103770 http://hdl.handle.net/10220/38794 |
| _version_ | 1826125033316024320 |
|---|---|
| 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 |
| 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 |
| author_sort | Wang, Qing-Yin |
| collection | NTU |
| 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. |
| first_indexed | 2024-10-01T06:30:07Z |
| format | Journal Article |
| id | ntu-10356/103770 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:30:07Z |
| publishDate | 2015 |
| record_format | dspace |
| spelling | ntu-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 |
| 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 |
| title | 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_short | Discovery of Dengue Virus NS4B Inhibitors |
| title_sort | discovery of dengue virus ns4b inhibitors |
| url | https://hdl.handle.net/10356/103770 http://hdl.handle.net/10220/38794 |
| work_keys_str_mv | AT wangqingyin discoveryofdenguevirusns4binhibitors AT donghongping discoveryofdenguevirusns4binhibitors AT zoubin discoveryofdenguevirusns4binhibitors AT karunaratna discoveryofdenguevirusns4binhibitors AT wankahfei discoveryofdenguevirusns4binhibitors AT zoujing discoveryofdenguevirusns4binhibitors AT susilaagatha discoveryofdenguevirusns4binhibitors AT yipandy discoveryofdenguevirusns4binhibitors AT shanchao discoveryofdenguevirusns4binhibitors AT yeokimlong discoveryofdenguevirusns4binhibitors AT xuhaoying discoveryofdenguevirusns4binhibitors AT dingmei discoveryofdenguevirusns4binhibitors AT chanwailing discoveryofdenguevirusns4binhibitors AT gufeng discoveryofdenguevirusns4binhibitors AT seahpeckgee discoveryofdenguevirusns4binhibitors AT liuwei discoveryofdenguevirusns4binhibitors AT lakshminarayanasureshb discoveryofdenguevirusns4binhibitors AT kangcongbao discoveryofdenguevirusns4binhibitors AT lescarjulien discoveryofdenguevirusns4binhibitors AT blascofrancesca discoveryofdenguevirusns4binhibitors AT smithpaulw discoveryofdenguevirusns4binhibitors AT shipeiyong discoveryofdenguevirusns4binhibitors |