https://scholars.lib.ntu.edu.tw/handle/123456789/623753
標題: | Tafenoquine and its derivatives as inhibitors for the severe acute respiratory syndrome coronavirus 2 | 作者: | Chen, Yeh Yang, Wen-Hao Chen, Hsiao-Fan LI-MIN HUANG Gao, Jing-Yan Lin, Cheng-Wen Wang, Yu-Chuan Yang, Chia-Shin Liu, Yi-Liang Hou, Mei-Hui Tsai, Chia-Ling Chou, Yi-Zhen Huang, Bao-Yue Hung, Chian-Fang Hung, Yu-Lin Wang, Wei-Jan Su, Wen-Chi Kumar, Vathan Wu, Yu-Chieh Chao, Shih-Wei Chang, Chih-Shiang JIN-SHING CHEN Chiang, Yu-Ping Cho, Der-Yang Jeng, Long-Bin Tsai, Chang-Hai Hung, Mien-Chie |
關鍵字: | COVID-19; SARS-CoV-2; TMPRSS2; drug action; drug design; drug discovery; main protease; tafenoquine; viral protease; virus entry | 公開日期: | 2022 | 出版社: | ELSEVIER | 卷: | 298 | 期: | 3 | 來源出版物: | The Journal of biological chemistry | 摘要: | The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has severely affected human lives around the world as well as the global economy. Therefore, effective treatments against COVID-19 are urgently needed. Here, we screened a library containing Food and Drug Administration (FDA)-approved compounds to identify drugs that could target the SARS-CoV-2 main protease (Mpro), which is indispensable for viral protein maturation and regard as an important therapeutic target. We identified antimalarial drug tafenoquine (TFQ), which is approved for radical cure of Plasmodium vivax and malaria prophylaxis, as a top candidate to inhibit Mpro protease activity. The crystal structure of SARS-CoV-2 Mpro in complex with TFQ revealed that TFQ noncovalently bound to and reshaped the substrate-binding pocket of Mpro by altering the loop region (residues 139-144) near the catalytic Cys145, which could block the catalysis of its peptide substrates. We also found that TFQ inhibited human transmembrane protease serine 2 (TMPRSS2). Furthermore, one TFQ derivative, compound 7, showed a better therapeutic index than TFQ on TMPRSS2 and may therefore inhibit the infectibility of SARS-CoV-2, including that of several mutant variants. These results suggest new potential strategies to block infection of SARS-CoV-2 and rising variants. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/623753 | ISSN: | 00219258 | DOI: | 10.1016/j.jbc.2022.101658 |
顯示於: | 醫學系 |
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