Institute of New Drug Development, China Medical University, Taichung, Taiwan; Drug Development Center, China Medical University, Taichung, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung, Taiwan.
Drug Development Center, China Medical University, Taichung, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Center for Molecular Medicine, China Medical University, Taichung, Taiwan.
J Biol Chem. 2022 Mar;298(3):101658. doi: 10.1016/j.jbc.2022.101658. Epub 2022 Jan 29.
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), 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 M protease activity. The crystal structure of SARS-CoV-2 M in complex with TFQ revealed that TFQ noncovalently bound to and reshaped the substrate-binding pocket of M 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.
由严重急性呼吸系统综合症冠状病毒 2（SARS-CoV-2）引起的大流行严重影响了全球人类的生活和全球经济。因此，急需有效的 COVID-19 治疗方法。在这里，我们筛选了一个包含美国食品和药物管理局（FDA）批准的化合物的文库，以确定能够靶向 SARS-CoV-2 主要蛋白酶（M）的药物，该酶对于病毒蛋白成熟是必不可少的，并且是一个重要的治疗靶标。我们确定了抗疟药物tafenoquine（TFQ）是抑制 M 蛋白酶活性的首选候选药物，TFQ 已被批准用于根治间日疟原虫和疟疾预防。SARS-CoV-2 M 与 TFQ 复合物的晶体结构表明，TFQ 通过改变靠近催化 Cys145 的环区域（残基 139-144），非共价结合并重塑 M 的底物结合口袋，从而可以阻止其肽底物的催化。我们还发现 TFQ 抑制了人类跨膜丝氨酸蛋白酶 2（TMPRSS2）。此外，TFQ 的一种衍生物，化合物 7，在 TMPRSS2 上的治疗指数优于 TFQ，因此可能抑制 SARS-CoV-2 的感染性，包括几种突变变体。这些结果表明了阻断 SARS-CoV-2 和不断出现的变体感染的新的潜在策略。
