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The main protease of SARS-CoV-2 (M\n                    <jats:sup>pro<\/jats:sup>\n                    ), critical for viral replication, is a key target for therapeutic development. An organoselenium drug called ebselen has been demonstrated to have potent M\n                    <jats:sup>pro<\/jats:sup>\n                    inhibition and antiviral activity. We have examined the binding modes of ebselen and its derivative in M\n                    <jats:sup>pro<\/jats:sup>\n                    via high resolution co-crystallography and investigated their chemical reactivity via mass spectrometry. Stronger M\n                    <jats:sup>pro<\/jats:sup>\n                    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\n                    <jats:sup>pro<\/jats:sup>\n                    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\n                    <jats:italic>beta<\/jats:italic>\n                    -corona viruses.\n                  <\/jats:p>","DOI":"10.1038\/s41467-021-23313-7","type":"journal-article","created":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T06:02:53Z","timestamp":1621836173000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":250,"title":["Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives"],"prefix":"10.1038","volume":"12","author":[{"given":"Kangsa","family":"Amporndanai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7774-2075","authenticated-orcid":false,"given":"Xiaoli","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijuan","family":"Shang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6448-820X","authenticated-orcid":false,"given":"Zhenmig","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Rogers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9866-2384","authenticated-orcid":false,"given":"Zihe","family":"Rao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7279-2893","authenticated-orcid":false,"given":"Zhi-Jie","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1875-3268","authenticated-orcid":false,"given":"Haitao","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2593-2571","authenticated-orcid":false,"given":"Leike","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4338-0317","authenticated-orcid":false,"given":"Paul M.","family":"O\u2019Neill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2854-4718","authenticated-orcid":false,"given":"S.","family":"Samar Hasnain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,24]]},"reference":[{"key":"23313_CR1","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/s41579-018-0118-9","volume":"17","author":"J Cui","year":"2019","unstructured":"Cui, J., Li, F. & Shi, Z. 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