{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T10:58:35Z","timestamp":1788692315285,"version":"build-2803163510"},"reference-count":65,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["GRK2873 (494832089)"],"award-info":[{"award-number":["GRK2873 (494832089)"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The severe acute respiratory syndrome coronavirus 2 (SARS\u2010CoV\u20102), causative agent of the coronavirus disease 2019 (COVID\u201019), is still circulating and posing a health threat to the global population. Its main protease (M\n                    <jats:sup>pro<\/jats:sup>\n                    ) constitutes an excellent target for the development of antivirals due to its indispensable role in the viral replication cycle. In this work, we employed a sequential approach to identify a potent azapeptide\u2010based M\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitor. Starting from a series of small\u2010molecule peptidomimetics, identical in their scaffold but equipped with different cysteine\u2010reactive groups, we identified auspicious warheads. The combination of selected moieties with an optimized, previously described P1\u2013P4 azapeptide structure resulted in a potent M\n                    <jats:sup>pro<\/jats:sup>\n                    inactivator (\n                    <jats:bold>12<\/jats:bold>\n                    ) with a\n                    <jats:italic>k<\/jats:italic>\n                    <jats:sub>inac<\/jats:sub>\n                    \/\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>i<\/jats:sub>\n                    value of 78,900\u2009M\n                    <jats:sup>\u20131<\/jats:sup>\n                    s\n                    <jats:sup>\u20131<\/jats:sup>\n                    . The chloracetohydrazide derivative\n                    <jats:bold>12<\/jats:bold>\n                    exhibited antiviral activity (EC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.47\u2009\u00b5M), no cytotoxicity, and plasma stability. The molecular interaction of\n                    <jats:bold>12<\/jats:bold>\n                    with M\n                    <jats:sup>pro<\/jats:sup>\n                    was elucidated by an X\u2010ray crystal structure. A thioether linkage was generated through a nucleophilic substitution of chloride by the active\u2010site thiolate, giving rise to irreversible inhibition.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70175","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T09:51:29Z","timestamp":1766483489000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Sequential Optimization Approach Toward an Azapeptide\u2010Based SARS\u2010CoV\u20102 Main Protease Inhibitor"],"prefix":"10.1002","volume":"358","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9249-8773","authenticated-orcid":false,"given":"Rabea","family":"Voget","sequence":"first","affiliation":[{"name":"Pharmaceutical Institute, Pharmaceutical &amp; Medicinal Chemistry University of Bonn Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7665-4523","authenticated-orcid":false,"given":"Victoria","family":"Steiger","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute, Pharmaceutical &amp; Medicinal Chemistry University of Bonn Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Breidenbach","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute, Pharmaceutical &amp; Medicinal Chemistry University of Bonn Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Sylvester","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute, Pharmaceutical &amp; Medicinal Chemistry University of Bonn Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christin","family":"M\u00fcller\u2010Ruttloff","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology Justus Liebig University Giessen Giessen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun\u2010Chiao","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Bioanalytical Chemistry, Center for Biotechnology and Biomedicine Leipzig University Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Ziebuhr","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology Justus Liebig University Giessen Giessen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Str\u00e4ter","sequence":"additional","affiliation":[{"name":"Institute of Bioanalytical Chemistry, Center for Biotechnology and Biomedicine Leipzig University Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christa E.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute, Pharmaceutical &amp; Medicinal Chemistry University of Bonn Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9376-7897","authenticated-orcid":false,"given":"Michael","family":"G\u00fctschow","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute, Pharmaceutical &amp; Medicinal Chemistry University of Bonn Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,23]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-023-00672-y"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2022.106201"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s43440-022-00394-9"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb3405"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-020-00689-z"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl4784"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2023.06.010"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacsau.4c00508"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2022.101144"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.202300301"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-31210-w"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c00551"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16954-7"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.2c00260"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adi0979"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.1c00910"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022.114570"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c00221"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.4c00024"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00665"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022.115021"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.3c00562"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200705858"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201101350"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202016961"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c00053"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.4c00096"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo020761f"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/cryst2031201"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2SC04147B"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c01081"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2024.105874"},{"key":"e_1_2_8_34_1","unstructured":"L. A.Miller Estervinylation of aromatic amines US3093679A June 11 1963."},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00505778"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1SC04247E"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2015.03.098"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.8b01259"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-018-0204-3"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1039\/D0SC03606D"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2024.03.001"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c00535"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.1c08060"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2023.104886"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(67)80055-X"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.1998.1038"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c01716"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c01661"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-021-00418-x"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2012-7"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adl4013"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiae385"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2603"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1135\/cccc19771069"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c01146"},{"key":"e_1_2_8_56_1","article-title":"Miniaturized Modular Click Chemistry\u2010Enabled Rapid Discovery of Unique SARS\u2010CoV\u20102 Mpro Inhibitors With Robust Potency and Drug\u2010Like Profile","volume":"11","author":"Yang M.","year":"2024","journal-title":"Advancement of Science"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444909047337"},{"key":"e_1_2_8_58_1","article-title":"Advances in Automated Data Analysis and Processing Within AutoPROC, Combined With Improved Characterisation, Mitigation and Visualisation of the Anisotropy of the Fraction Limits Using STARANISO","volume":"74","author":"Vonrhein C.","year":"2018","journal-title":"Acta Crystallographica"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr535"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1107\/S2059798319011471"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2021.167118"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444910007493"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.052"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2020.104706"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01463-17"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2017.12.010"}],"container-title":["Archiv der Pharmazie"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ardp.70175","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ardp.70175","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ardp.70175","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T16:26:46Z","timestamp":1772987206000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ardp.70175"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":65,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/ardp.70175"],"URL":"https:\/\/doi.org\/10.1002\/ardp.70175","archive":["Portico"],"relation":{},"ISSN":["0365-6233","1521-4184"],"issn-type":[{"value":"0365-6233","type":"print"},{"value":"1521-4184","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12]]},"assertion":[{"value":"2025-08-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70175"}}