tetano
Editor, Senior Moderator
J Biol Chem
. 2022 Jan 28;101658.
doi: 10.1016/j.jbc.2022.101658. Online ahead of print.
Tafenoquine and its derivatives as inhibitors for the Severe Acute Respiratory Syndrome Coronavirus 2
Yeh Chen[SUP] 1 [/SUP], Wen-Hao Yang[SUP] 2 [/SUP], Hsiao-Fan Chen[SUP] 3 [/SUP], Li-Min Huang[SUP] 4 [/SUP], Jing-Yan Gao[SUP] 5 [/SUP], Cheng-Wen Lin[SUP] 6 [/SUP], Yu-Chuan Wang[SUP] 7 [/SUP], Chia-Shin Yang[SUP] 7 [/SUP], Yi-Liang Liu[SUP] 8 [/SUP], Mei-Hui Hou[SUP] 7 [/SUP], Chia-Ling Tsai[SUP] 7 [/SUP], Yi-Zhen Chou[SUP] 7 [/SUP], Bao-Yue Huang[SUP] 3 [/SUP], Chian-Fang Hung[SUP] 3 [/SUP], Yu-Lin Hung[SUP] 9 [/SUP], Wei-Jan Wang[SUP] 10 [/SUP], Wen-Chi Su[SUP] 3 [/SUP], Vathan Kumar[SUP] 11 [/SUP], Yu-Chieh Wu[SUP] 12 [/SUP], Shih-Wei Chao[SUP] 11 [/SUP], Chih-Shiang Chang[SUP] 5 [/SUP], Jin-Shing Chen[SUP] 13 [/SUP], Yu-Ping Chiang[SUP] 4 [/SUP], Der-Yang Cho[SUP] 14 [/SUP], Long-Bin Jeng[SUP] 15 [/SUP], Chang-Hai Tsai[SUP] 16 [/SUP], Mien-Chie Hung[SUP] 17 [/SUP]
Affiliations
Abstract
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 (M[SUP]pro[/SUP]), which is indispensable for viral protein maturation and regard as an important therapeutic target. We identified anti-malarial drug tafenoquine (TFQ), which is approved for radical cure of Plasmodium vivax and malaria prophylaxis, as a top candidate to inhibit M[SUP]pro[/SUP] protease activity. The crystal structure of SARS-CoV-2 M[SUP]pro[/SUP] in complex with TFQ revealed that TFQ noncovalently bound to and reshaped the substrate binding pocket of M[SUP]pro[/SUP] 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.
. 2022 Jan 28;101658.
doi: 10.1016/j.jbc.2022.101658. Online ahead of print.
Tafenoquine and its derivatives as inhibitors for the Severe Acute Respiratory Syndrome Coronavirus 2
Yeh Chen[SUP] 1 [/SUP], Wen-Hao Yang[SUP] 2 [/SUP], Hsiao-Fan Chen[SUP] 3 [/SUP], Li-Min Huang[SUP] 4 [/SUP], Jing-Yan Gao[SUP] 5 [/SUP], Cheng-Wen Lin[SUP] 6 [/SUP], Yu-Chuan Wang[SUP] 7 [/SUP], Chia-Shin Yang[SUP] 7 [/SUP], Yi-Liang Liu[SUP] 8 [/SUP], Mei-Hui Hou[SUP] 7 [/SUP], Chia-Ling Tsai[SUP] 7 [/SUP], Yi-Zhen Chou[SUP] 7 [/SUP], Bao-Yue Huang[SUP] 3 [/SUP], Chian-Fang Hung[SUP] 3 [/SUP], Yu-Lin Hung[SUP] 9 [/SUP], Wei-Jan Wang[SUP] 10 [/SUP], Wen-Chi Su[SUP] 3 [/SUP], Vathan Kumar[SUP] 11 [/SUP], Yu-Chieh Wu[SUP] 12 [/SUP], Shih-Wei Chao[SUP] 11 [/SUP], Chih-Shiang Chang[SUP] 5 [/SUP], Jin-Shing Chen[SUP] 13 [/SUP], Yu-Ping Chiang[SUP] 4 [/SUP], Der-Yang Cho[SUP] 14 [/SUP], Long-Bin Jeng[SUP] 15 [/SUP], Chang-Hai Tsai[SUP] 16 [/SUP], Mien-Chie Hung[SUP] 17 [/SUP]
Affiliations
- PMID: 35101449
- DOI: 10.1016/j.jbc.2022.101658
Abstract
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 (M[SUP]pro[/SUP]), which is indispensable for viral protein maturation and regard as an important therapeutic target. We identified anti-malarial drug tafenoquine (TFQ), which is approved for radical cure of Plasmodium vivax and malaria prophylaxis, as a top candidate to inhibit M[SUP]pro[/SUP] protease activity. The crystal structure of SARS-CoV-2 M[SUP]pro[/SUP] in complex with TFQ revealed that TFQ noncovalently bound to and reshaped the substrate binding pocket of M[SUP]pro[/SUP] 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.