Tafenoquine and its derivatives as inhibitors for the severe acute respiratory syndrome coronavirus 2
Journal
The Journal of biological chemistry
Journal Volume
298
Journal Issue
3
Date Issued
2022
Author(s)
Chen, Yeh
Yang, Wen-Hao
Chen, Hsiao-Fan
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
Chiang, Yu-Ping
Cho, Der-Yang
Jeng, Long-Bin
Tsai, Chang-Hai
Hung, Mien-Chie
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 (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.
Subjects
COVID-19; SARS-CoV-2; TMPRSS2; drug action; drug design; drug discovery; main protease; tafenoquine; viral protease; virus entry
SDGs
Publisher
ELSEVIER
Type
journal article