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.
【저자키워드】 X-ray crystallography, Drug discovery and development, 【초록키워드】 viruses, SARS-CoV-2, pandemic, protease, antiviral activity, viral replication, zoonotic, therapeutic, Ebselen, Critical, mechanism, Analysis, crystal structures, cysteine, enzyme, M pro, catalytic dyad, infected cell, crystallographic structure, derivatives, hydrolysis, develop, examined, investigated, inhibit, demonstrated, these compound, triggered, reactivity, binding mode, global effort, the SARS-CoV-2, 【제목키워드】 inhibition, SARS-CoV-2 main protease, Ebselen, mechanism, derivative,