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Please use this identifier to cite or link to this item:
http://ir.nhri.org.tw/handle/3990099045/12221
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| Title: | A novel flavivirus entry inhibitor, BP34610, discovered through high-throughput screening with dengue reporter viruses |
| Authors: | Yang, CC;Hu, HS;Lin, HM;Wu, PS;Wu, RH;Tian, JN;Wu, SH;Tsou, LK;Song, JS;Chen, HW;Chern, JH;Chen, CT;Yueh, A |
| Contributors: | Institute of Biotechnology and Pharmaceutical Research;National Institute of Infectious Diseases and Vaccinology |
| Abstract: | Dengue virus (DENV) is a global health problem that affects approximately 3.9 billion people worldwide. Since safety concerns were raised for the only licensed vaccine, Dengvaxia, and since the present treatment is only supportive care, the development of more effective therapeutic anti-DENV agents is urgently needed. In this report, we identified a potential small-molecule inhibitor, BP34610, via cell-based high-throughput screening (HTS) of 12,000 compounds using DENV-2 reporter viruses. BP34610 reduced the virus yields of type 2 DENV-infected cells with a 50% effective concentration (EC50) and selectivity index value of 0.48+/-0.06muM and 197, respectively. Without detectable cytotoxicity, the compound inhibited not only all four serotypes of DENV but also Japanese encephalitis virus (JEV). Time-of-addition experiments suggested that BP34610 may act at an early stage of DENV virus infection. Sequencing analyses of several individual clones derived from BP34610-resistant viruses revealed a consensus amino acid substitution (S397P) in the N-terminal stem region of the E protein. Introduction of S397P into the DENV reporter viruses conferred an over 14.8-fold EC90 shift for BP34610. Importantly, the combination of BP34610 with a viral replication inhibitor, ribavirin, displayed synergistic enhancement of anti-DENV-2 activity. Our results identify an effective small-molecule inhibitor, BP34610, which likely targets the DENV E protein. BP34610 could be developed as an anti-flavivirus agent in the future. |
| Date: | 2019-12 |
| Relation: | Antiviral Research. 2019 Dec;172:Article number 104636. |
| Link to: | http://dx.doi.org/10.1016/j.antiviral.2019.104636 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0166-3542&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000499939700010 |
| Cited Times(Scopus): | https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85074720028 |
| Appears in Collections: | [岳嶽] 期刊論文
[陳炯東] 期刊論文
[陳志豪] 期刊論文
[鄒倫] 期刊論文
[陳信偉] 期刊論文
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| PUB31654671.pdf | 3704Kb | Adobe PDF | 303 | View/Open |
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