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

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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) , Hasnain, S Samar and Rogers, Michael (2021) Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives. NATURE COMMUNICATIONS, 12 (1). 3061-.

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Official URL: http://dx.doi.org/10.1038/s41467-021-23313-7

Abstract

The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease of SARS-CoV-2 (Mpro), critical for viral replication, is a key target for therapeutic development. An organoselenium drug called ebselen has been demonstrated to have potent Mpro inhibition and antiviral activity. We have examined the binding modes of ebselen and its derivative in Mpro via high resolution co-crystallography and investigated their chemical reactivity via mass spectrometry. Stronger Mpro 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 Mpro 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
Open Access URL:	https://doi.org/10.1038/s41467-021-23313-7
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3126337