1. Tafenoquine and its derivatives as inhibitors for the severe acute respiratory syndrome coronavirus 2.
- Author
-
Chen Y, Yang WH, Chen HF, Huang LM, Gao JY, Lin CW, Wang YC, Yang CS, Liu YL, Hou MH, Tsai CL, Chou YZ, Huang BY, Hung CF, Hung YL, Wang WJ, Su WC, Kumar V, Wu YC, Chao SW, Chang CS, Chen JS, Chiang YP, Cho DY, Jeng LB, Tsai CH, and Hung MC
- Subjects
- Humans, Molecular Docking Simulation, Pandemics, Protease Inhibitors chemistry, Protease Inhibitors pharmacology, Virus Internalization drug effects, Aminoquinolines chemistry, Aminoquinolines pharmacology, Antiviral Agents chemistry, Antiviral Agents pharmacology, Coronavirus 3C Proteases antagonists & inhibitors, SARS-CoV-2 drug effects, SARS-CoV-2 enzymology, COVID-19 Drug Treatment
- 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
pro ), 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., Competing Interests: Conflict of interest The authors declare that there is no conflict of interests with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
- Full Text
- View/download PDF