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In this study, focused compound libraries are synthesized in 96\u2010 well plates utilizing modular click chemistry to rapidly discover potent inhibitors targeting the main protease (M<jats:sup>pro<\/jats:sup>) of SARS\u2010CoV\u20102. Subsequent direct biological screening identifies novel 1,2,3\u2010triazole derivatives as robust M<jats:sup>pro<\/jats:sup> inhibitors with high anti\u2010SARS\u2010CoV\u20102 activity. Notably, <jats:bold>C5N17B<\/jats:bold> demonstrates sub\u2010micromolar M<jats:sup>pro<\/jats:sup> inhibitory potency (IC<jats:sub>50<\/jats:sub> = 0.12 \u00b5M) and excellent antiviral activity in Calu\u20103 cells determined in an immunofluorescence\u2010based antiviral assay (EC<jats:sub>50<\/jats:sub> = 0.078 \u00b5M, no cytotoxicity: CC<jats:sub>50<\/jats:sub> &gt; 100 \u00b5M). <jats:bold>C5N17B<\/jats:bold> shows superior potency to nirmatrelvir (EC<jats:sub>50<\/jats:sub> = 1.95 \u00b5M) and similar efficacy to ensitrelvir (EC<jats:sub>50<\/jats:sub> = 0.11 \u00b5M). Importantly, this compound displays high antiviral activities against several SARS\u2010CoV\u20102 variants (Gamma, Delta, and Omicron, EC<jats:sub>50<\/jats:sub> = 0.13 \u2013 0.26 \u00b5M) and HCoV\u2010OC43, indicating its broad\u2010spectrum antiviral activity. It is worthy that <jats:bold>C5N17B<\/jats:bold> retains antiviral activity against nirmatrelvir\u2010resistant strains with T21I\/E166V and L50F\/E166V mutations in M<jats:sup>pro<\/jats:sup> (EC<jats:sub>50<\/jats:sub> = 0.26 and 0.15 \u00b5M, respectively). Furthermore, <jats:bold>C5N17B<\/jats:bold> displays favorable pharmacokinetic properties. Crystallography studies reveal a unique, non\u2010covalent multi\u2010site binding mode. In conclusion, these findings substantiate the potential of <jats:bold>C5N17B<\/jats:bold> as an up\u2010and\u2010coming drug candidate targeting SARS\u2010CoV\u20102 M<jats:sup>pro<\/jats:sup> for clinical therapy.<\/jats:p>","DOI":"10.1002\/advs.202404884","type":"journal-article","created":{"date-parts":[[2024,9,25]],"date-time":"2024-09-25T11:19:43Z","timestamp":1727263183000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Miniaturized Modular Click Chemistry\u2010enabled Rapid Discovery of Unique SARS\u2010CoV\u20102 M<sup>pro<\/sup> Inhibitors With Robust Potency and Drug\u2010like Profile"],"prefix":"10.1002","volume":"11","author":[{"given":"Mianling","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry Key Laboratory of Chemical Biology Ministry of Education School of Pharmaceutical Sciences Shandong University  Ji'nan 250012 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myoung Kyu","family":"Lee","sequence":"additional","affiliation":[{"name":"Infectious Diseases Therapeutic Research Center Korea Research Institute of Chemical Technology (KRICT)  Daejeon 34114 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenghua","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Key Laboratory of Chemical Biology Ministry of Education School of Pharmaceutical Sciences Shandong University  Ji'nan 250012 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Letian","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Key Laboratory of Chemical Biology Ministry of Education School of Pharmaceutical Sciences Shandong University  Ji'nan 250012 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye\u2010Yeon","family":"Jang","sequence":"additional","affiliation":[{"name":"Infectious Diseases Therapeutic Research Center Korea Research Institute of Chemical Technology (KRICT)  Daejeon 34114 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inseong","family":"Jo","sequence":"additional","affiliation":[{"name":"Infectious Diseases Therapeutic Research Center Korea Research Institute of Chemical Technology (KRICT)  Daejeon 34114 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun\u2010Chiao","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Bioanalytical Chemistry Leipzig University  Deutscher Platz 5 04103 Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Sylvester","sequence":"additional","affiliation":[{"name":"PharmaCenter Bonn &amp; 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