Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives

Amporndanai, Kangsa, Meng, Xiaoli ORCID: 0000-0002-7774-2075, Shang, Weijuan, Jin, Zhenmig, Zhao, Yao, Rao, Zihe, Liu, Zhi-Jie, Yang, Haitao, Zhang, Leike, O'Neill, Paul M ORCID: 0000-0003-4338-0317
et al (show 2 more authors) (2021) Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives. NATURE COMMUNICATIONS, 12 (1). 3061-.

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The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease of SARS-CoV-2 (M<sup>pro</sup>), critical for viral replication, is a key target for therapeutic development. An organoselenium drug called ebselen has been demonstrated to have potent M<sup>pro</sup> inhibition and antiviral activity. We have examined the binding modes of ebselen and its derivative in M<sup>pro</sup> via high resolution co-crystallography and investigated their chemical reactivity via mass spectrometry. Stronger M<sup>pro</sup> inhibition than ebselen and potent ability to rescue infected cells were observed for a number of derivatives. A free selenium atom bound with cysteine of catalytic dyad has been revealed in crystallographic structures of M<sup>pro</sup> with ebselen and MR6-31-2 suggesting hydrolysis of the enzyme bound organoselenium covalent adduct and formation of a phenolic by-product, confirmed by mass spectrometry. The target engagement with selenation mechanism of inhibition suggests wider therapeutic applications of these compounds against SARS-CoV-2 and other zoonotic beta-corona viruses.

Item Type: Article
Uncontrolled Keywords: Selenium, Salicylanilides, Organoselenium Compounds, Cysteine, Azoles, Protease Inhibitors, Antiviral Agents, Crystallography, X-Ray, Catalytic Domain, Hydrolysis, Models, Molecular, Reference Standards, Isoindoles, SARS-CoV-2, Coronavirus 3C Proteases
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Faculty of Science and Engineering > School of Physical Sciences
Depositing User: Symplectic Admin
Date Deposited: 15 Jun 2021 07:42
Last Modified: 17 Feb 2023 23:03
DOI: 10.1038/s41467-021-23313-7
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