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

• Published in: Nature communications Vol. 12; no. 1; pp. 3061 - 7
• Main Authors: Amporndanai, Kangsa, Meng, Xiaoli, Shang, Weijuan, Jin, Zhenmig, Rogers, Michael, Zhao, Yao, Rao, Zihe, Liu, Zhi-Jie, Yang, Haitao, Zhang, Leike, O’Neill, Paul M., Samar Hasnain, S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.05.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 101/58; 631/154/309/2144; 631/535/1266; Antiviral activity; Antiviral drugs; Chemical compounds; Chemical reactions; COVID-19; Crystal structure; Crystallography; Enzymes; Humanities and Social Sciences; Mass spectrometry; Mass spectroscopy; multidisciplinary; Pandemics; Pharmacology; Phenolic compounds; Phenols; Protease; Proteinase; Science; Science (multidisciplinary); Scientific imaging; Selenium; Severe acute respiratory syndrome coronavirus 2; Spectroscopy; Therapeutic applications; Viral diseases
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23313-7

The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease of SARS-CoV-2 (M pro ), critical for viral replication, is a key target for therapeutic development. An organoselenium drug called ebselen has been demonstrated to have potent M pro inhibition and antiviral activity. We have examined the binding modes of ebselen and its derivative in M pro via high resolution co-crystallography and investigated their chemical reactivity via mass spectrometry. Stronger M pro 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 pro 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. Ebselen is an organoselenium drug that inhibits the SARS-CoV-2 main protease (M pro ). Here, the authors co-crystallised M pro with ebselen and an ebselen derivative and observed an enzyme bound organoselenium covalent adduct in the crystal structures, which was also confirmed by mass spectrometry analysis.