Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34031399.
- Also identified by DOI 10.1038/s41467-021-23313-7 and PMC identifier 8144557.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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.
Medical subject headings
- Azoles
- Coronavirus 3C Proteases
- Organoselenium Compounds
- SARS-CoV-2