{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T05:07:07Z","timestamp":1779772027866,"version":"3.53.1"},"reference-count":54,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,5,14]]},"abstract":"<jats:p>\n                    Despite the availability of vaccines and antiviral drugs, SARS\u2010CoV\u20102 still presents a global health threat, emphasizing the need for new therapeutic targets beyond the main protease and RNA\u2010dependent RNA polymerase. The papain\u2010like protease (PL\n                    <jats:sup>pro<\/jats:sup>\n                    ) is a highly conserved and essential viral enzyme that drives polyprotein processing and suppresses host innate immune responses through its deubiquitinating and deISGylating activities. This study employed two approaches to identify new PL\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitors: (i) the design and synthesis of a range of non\u2010covalent PL\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitors based on a lead compound, GRL0617. (ii) Screening the in\u2010house library for new covalent PL\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitors. Biochemical assays demonstrated effective inhibition of PL\n                    <jats:sup>pro<\/jats:sup>\n                    activity, particularly with the non\u2010covalent inhibitor\n                    <jats:bold>2t<\/jats:bold>\n                    (\n                    <jats:bold>TPG\u20102t<\/jats:bold>\n                    , IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.634\u2009\u00b5M) and with potential covalent inhibitors such as\n                    <jats:bold>13e<\/jats:bold>\n                    (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u200922.0\u2009\u00b5M) and\n                    <jats:bold>13f<\/jats:bold>\n                    (\n                    <jats:bold>TPG\u201013f<\/jats:bold>\n                    , IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20095.0\u2009\u00b5M).\n                    <jats:bold>2t<\/jats:bold>\n                    exhibited antiviral activity (EC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20092.89\u2009\u00b5M) without causing cellular toxicity. Molecular modeling suggests that\n                    <jats:bold>2t<\/jats:bold>\n                    can establish stable binding interactions within the PL\n                    <jats:sup>pro<\/jats:sup>\n                    active site. Therefore, inhibitor\n                    <jats:bold>2t<\/jats:bold>\n                    could be a promising candidate for future antiviral development.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202600007","type":"journal-article","created":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T04:16:27Z","timestamp":1778300187000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibitors Targeting SARS\u2010CoV\u20102 Papain\u2010Like Protease: Screening, Design, Synthesis, and Biological Evaluation"],"prefix":"10.1002","volume":"21","author":[{"given":"Elena\u2010Oriana","family":"Iuga","sequence":"first","affiliation":[{"name":"Institute of Pharmacy Pharmaceutical\/Medicinal Chemistry Eberhard Karls University  T\u00fcbingen Germany"},{"name":"T\u00fcbingen Center for Academic Drug Discovery (T\u00fcCAD<sub>2<\/sub>) Eberhard Karls University  T\u00fcbingen 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Agostinetto","sequence":"additional","affiliation":[{"name":"Faculdade de Farm\u00e1cia Universidade Federal do Rio Grande do Sul  Porto Alegre Brazil"},{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liam","family":"Urich","sequence":"additional","affiliation":[{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Kr\u00fcger","sequence":"additional","affiliation":[{"name":"Platform Infection Models German Primate Center Leibniz Institute for Primate Research G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thales","family":"Kronenberger","sequence":"additional","affiliation":[{"name":"School of Pharmacy Faculty of Health Sciences University of Eastern Finland  Kuopio Finland"},{"name":"German Center for Infection Research (DZIF), partner\u2010site T\u00fcbingen Institute of Medical Microbiology and Hygiene Interfaculty Institute of Microbiology and Infection Medicine (IMIT) University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael Victorio Carvalho","family":"Guido","sequence":"additional","affiliation":[{"name":"S\u00e3o Carlos Institute of Physics University of S\u00e3o Paulo (USP)  S\u00e3o Carlos Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J.","family":"O\u2019Donoghue","sequence":"additional","affiliation":[{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan A.","family":"Laufer","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy Pharmaceutical\/Medicinal 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