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PL\n                    <jats:sup>pro<\/jats:sup>\n                    and M\n                    <jats:sup>pro<\/jats:sup>\n                    are medicinal chemistry targets, with M\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitors being used for COVID\u201019 treatment. PL\n                    <jats:sup>pro<\/jats:sup>\n                    also catalyzes hydrolysis of ubiquitin and interferon\u2010stimulated gene 15 (ISG15) from post\u2010translationally modified human proteins. Here we report how screening of reported deubiquitinase inhibitors using solid\u2010phase extraction coupled to mass spectrometry assays with oligopeptide substrates based on pp1a\/1ab and on an ISG15\u2010modified human protein enabled the identification of substrate\u2010selective PL\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitors. The results reveal that the deubiquitinase inhibitor ML364 selectively inhibits the deISGylase activity of isolated PL\n                    <jats:sup>pro<\/jats:sup>\n                    over its pp1a\/1ab\u2010processing activity. Structure\u2010activity relationship and computational studies support the assignment of ML364 and derivatives as substrate\u2010selective PL\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitors. The combined results provide proof\u2010of\u2010concept for developing substrate\u2010selective inhibitors of PL\n                    <jats:sup>pro<\/jats:sup>\n                    and, by implication, related proteolytic enzymes, including deubiquitinases.\n                  <\/jats:p>","DOI":"10.1002\/chem.71248","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T10:45:49Z","timestamp":1781261149000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Substrate\u2010Selective Inhibition of the SARS\u2010CoV\u20102 Papain\u2010Like Protease: Inhibition of Hydrolysis of Human Over Viral Substrates"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2407-583X","authenticated-orcid":false,"given":"Sakshi","family":"Sharma","sequence":"first","affiliation":[{"name":"Chemistry Research Laboratory and the Ineos Oxford Institute for Antimicrobial Research University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2354-3281","authenticated-orcid":false,"given":"Peter A. 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