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Current inhibitors of SARS main protease, including the clinically admitted drug nirmatrelvir are peptidomimetics with the downsides of this class of drugs including limited oral bioavailability, cellular permeability, and rapid metabolic degradation. Here, we investigate covalent fragment inhibitors of SARS M<jats:sup>pro<\/jats:sup> as potential alternatives to peptidomimetic inhibitors in use today. Starting from inhibitors acylating the enzyme's active site, a set of reactive fragments was synthesized, and the inhibitory potency was correlated with the chemical stability of the inhibitors and the kinetic stability of the covalent enzyme\u2010inhibitor complex. We found that all tested acylating carboxylates, several of them published prominently, were hydrolyzed in assay buffer and the inhibitory acyl\u2010enzyme complexes were rapidly degraded leading to the irreversible inactivation of these drugs. Acylating carbonates were found to be more stable than acylating carboxylates, however, were inactive in infected cells. Finally, reversibly covalent fragments were investigated as chemically stable SARS CoV\u20102 inhibitors. Best was a pyridine\u2010aldehyde fragment with an IC<jats:sub>50<\/jats:sub> of 1.8\u2005\u03bcM at a molecular weight of 211\u2005g\/mol, showing that pyridine fragments indeed are able to block the active site of SARS\u2010CoV\u20102 main protease.<\/jats:p>","DOI":"10.1002\/cmdc.202200635","type":"journal-article","created":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T12:24:40Z","timestamp":1677068680000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A Critical Study on Acylating and Covalent Reversible Fragment Inhibitors of SARS\u2010CoV\u20102 Main Protease Targeting the S1 Site with Pyridine"],"prefix":"10.1002","volume":"18","author":[{"given":"Rebekka","family":"Wamser","sequence":"first","affiliation":[{"name":"Department of Biology Chemistry and Pharmacy Institute of Pharmacy Freie Universit\u00e4t Berlin  K\u00f6nigin-Luise-Str.2+4 14195 Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Szymon","family":"Pach","sequence":"additional","affiliation":[{"name":"Department of Biology Chemistry and Pharmacy Institute of Pharmacy Freie Universit\u00e4t Berlin  K\u00f6nigin-Luise-Str.2+4 14195 Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Arkona","sequence":"additional","affiliation":[{"name":"Department of Biology Chemistry and Pharmacy Institute of Pharmacy Freie Universit\u00e4t Berlin  K\u00f6nigin-Luise-Str.2+4 14195 Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morris","family":"Baumgardt","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Respiratory Medicine and Critical Care Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin  Charit\u00e9platz 1 10117 Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umer Bin Abdul","family":"Aziz","sequence":"additional","affiliation":[{"name":"Department of Biology Chemistry and Pharmacy Institute of Pharmacy Freie Universit\u00e4t Berlin  K\u00f6nigin-Luise-Str.2+4 14195 Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas C.","family":"Hocke","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Respiratory Medicine and Critical Care Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin  Charit\u00e9platz 1 10117 Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Wolber","sequence":"additional","affiliation":[{"name":"Department of Biology Chemistry and Pharmacy Institute of Pharmacy Freie Universit\u00e4t Berlin  K\u00f6nigin-Luise-Str.2+4 14195 Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6678-3165","authenticated-orcid":false,"given":"J\u00f6rg","family":"Rademann","sequence":"additional","affiliation":[{"name":"Department of Biology Chemistry and Pharmacy Institute of Pharmacy Freie Universit\u00e4t Berlin  K\u00f6nigin-Luise-Str.2+4 14195 Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,3,13]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2223-y"},{"key":"e_1_2_9_2_1","unstructured":"\u00a0"},{"key":"e_1_2_9_3_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.AC120.016154"},{"key":"e_1_2_9_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2008-3"},{"key":"e_1_2_9_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2012-7"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.0c03420"},{"key":"e_1_2_9_7_1","unstructured":"\u00a0"},{"key":"e_1_2_9_8_2","unstructured":"M.\u2005J. 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