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The viral main protease (M\n                    <jats:sup>pro<\/jats:sup>\n                    ) represents one of the most attractive targets for the development of antiviral drugs. Herein we report peptidyl nitroalkenes exhibiting enzyme inhibitory activity against M\n                    <jats:sup>pro<\/jats:sup>\n                    (\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>i<\/jats:italic>\n                    <\/jats:sub>\n                    : 1\u201310\u2009\u03bcM) good anti-SARS-CoV-2 infection activity in the low micromolar range (EC\n                    <jats:sub>50<\/jats:sub>\n                    : 1\u201312\u2009\u03bcM) without significant toxicity. Additional kinetic studies of compounds\n                    <jats:bold>FGA145<\/jats:bold>\n                    ,\n                    <jats:bold>FGA146<\/jats:bold>\n                    and\n                    <jats:bold>FGA147<\/jats:bold>\n                    show that all three compounds inhibit cathepsin L, denoting a possible multitarget effect of these compounds in the antiviral activity. Structural analysis shows the binding mode of\n                    <jats:bold>FGA146<\/jats:bold>\n                    and\n                    <jats:bold>FGA147<\/jats:bold>\n                    to the active site of the protein. Furthermore, our results illustrate that peptidyl nitroalkenes are effective covalent reversible inhibitors of the M\n                    <jats:sup>pro<\/jats:sup>\n                    and cathepsin L, and that inhibitors\n                    <jats:bold>FGA145<\/jats:bold>\n                    ,\n                    <jats:bold>FGA146<\/jats:bold>\n                    and\n                    <jats:bold>FGA147<\/jats:bold>\n                    prevent infection against SARS-CoV-2.\n                  <\/jats:p>","DOI":"10.1038\/s42004-024-01104-7","type":"journal-article","created":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T00:02:20Z","timestamp":1705536140000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Peptidyl nitroalkene inhibitors of main protease rationalized by computational and crystallographic investigations as antivirals against SARS-CoV-2"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8185-9751","authenticated-orcid":false,"given":"Francisco J.","family":"Medrano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1087-7143","authenticated-orcid":false,"given":"Sergio","family":"de la Hoz-Rodr\u00edguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Mart\u00ed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kemel","family":"Arafet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Schirmeister","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0769-8435","authenticated-orcid":false,"given":"Stefan J.","family":"Hammerschmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6444-9478","authenticated-orcid":false,"given":"Christin","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1gueda","family":"Gonz\u00e1lez-Mart\u00ednez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Santillana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5741-8825","authenticated-orcid":false,"given":"John","family":"Ziebuhr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6990-6973","authenticated-orcid":false,"given":"Antonio","family":"Romero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Collin","family":"Zimmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5016-0286","authenticated-orcid":false,"given":"Annabelle","family":"Weldert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Zimmermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8675-1002","authenticated-orcid":false,"given":"Alessio","family":"Lodola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7528-1551","authenticated-orcid":false,"given":"Katarzyna","family":"\u015awiderek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3665-3391","authenticated-orcid":false,"given":"Vicent","family":"Moliner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5709-734X","authenticated-orcid":false,"given":"Florenci V.","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,1,18]]},"reference":[{"key":"1104_CR1","unstructured":"World Health Organization. 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