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

Kangsa Amporndanai, Xiaoli Meng, Weijuan Shang, Zhenmig Jin, Michael Rogers, Yao Zhao, Zihe Rao, Zhi-Jie Liu, Haitao Yang (), Leike Zhang (), Paul M. O’Neill () and S. Samar Hasnain ()
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Kangsa Amporndanai: University of Liverpool
Xiaoli Meng: University of Liverpool
Weijuan Shang: Chinese Academy of Sciences
Zhenmig Jin: ShanghaiTech University
Michael Rogers: University of Liverpool
Yao Zhao: ShanghaiTech University
Zihe Rao: ShanghaiTech University
Zhi-Jie Liu: ShanghaiTech University
Haitao Yang: ShanghaiTech University
Leike Zhang: Chinese Academy of Sciences
Paul M. O’Neill: University of Liverpool
S. Samar Hasnain: University of Liverpool

Nature Communications, 2021, vol. 12, issue 1, 1-7

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23313-7

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