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

DOI: 10.1038/s41467-021-23313-7 DOI Help

Authors: Kangsa Amporndanai (University of Liverpool) , Xiaoli Meng (University of Liverpool) , Weijuan Shang (Wuhan Institute of Virology, 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 (Wuhan Institute of Virology, Chinese Academy of Sciences) , Paul M. O’neill (University of Liverpool) , S. Samar Hasnain (University of Liverpool)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 12

State: Published (Approved)
Published: May 2021
Diamond Proposal Number(s): 27113

Open Access Open Access

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.

Journal Keywords: Drug discovery and development

Diamond Keywords: COVID-19; Viruses

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-Macromolecular Crystallography

Added On: 30/05/2021 17:34


Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)