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The development of potent next-generation Mpro inhibitors is of great importance to ensure the availability of safe and effective COVID-19 therapeutics. Associated research necessitates robust and highly sensitive biochemical assays for the early kinetic characterization of Mpro inhibitor candidates. These assays often reach their limits when characterizing highly potent inhibitors, with a common bottleneck being the insufficient catalytic efficiency and competitive capacity of employed Mpro substrates. To optimize assays for highly active Mpro inhibitors by providing Mpro substrates with improved kinetic features, we created a library of fluorogenic substrates (2\u20138). These reporters were structurally derived from the well-established Mpro substrate Boc-Abu-Tle-Leu-Gln-AMC (1) and the clinically approved covalent-reversible Mpro inhibitor nirmatrelvir. Kinetic evaluation of 1\u20138 identified hit compound 6 with about ten-fold improved catalytic efficiency (kcat\/Km = 21,400 M\u20131 s\u20131) compared to parent substrate 1 (kcat\/Km = 2410 M\u20131 s\u20131). Substrate 6 was successfully applied for the kinetic characterization of three highly potent Mpro inhibitors. Comparative X-ray crystallographic analyses revealed high similarity in the molecular interactions of the C145A mutant Mpro with nirmatrelvir and with a peptide whose sequence was derived from a natural Mpro substrate. The tetrapeptidic AMC derivative 6 will serve as a valuable biochemical tool contributing to the optimization of SARS-CoV-2 Mpro-directed drug research.<\/jats:p>","DOI":"10.1021\/acschembio.6c00577","type":"journal-article","created":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T03:01:16Z","timestamp":1788663676000},"page":"2451-2465","source":"Crossref","is-referenced-by-count":0,"title":["From Inhibitor to Reporter: Nirmatrelvir-Derived Fluorogenic Substrates for the SARS-CoV-2 Main Protease"],"prefix":"10.1021","volume":"21","author":[{"given":"Rabea","family":"Voget","sequence":"first","affiliation":[{"name":"University of Bonn , , An der Immenburg 4 , ,","place":["Bonn, Germany, 53121"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Steiger","sequence":"additional","affiliation":[{"name":"University of Bonn , , An der Immenburg 4 , ,","place":["Bonn, Germany, 53121"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Sylvester","sequence":"additional","affiliation":[{"name":"University of Bonn , , An der Immenburg 4 , ,","place":["Bonn, Germany, 53121"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Chiao","family":"Yang","sequence":"additional","affiliation":[{"name":"Leipzig University , , ,","place":["Leipzig, Germany, 04103"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louisa von","family":"Kohout","sequence":"additional","affiliation":[{"name":"University of Bonn , , An der Immenburg 4 , ,","place":["Bonn, Germany, 53121"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Thimm","sequence":"additional","affiliation":[{"name":"University of Bonn , , An der Immenburg 4 , ,","place":["Bonn, Germany, 53121"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Breidenbach","sequence":"additional","affiliation":[{"name":"University of Bonn , , An der Immenburg 4 , ,","place":["Bonn, Germany, 53121"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2001-0500","authenticated-orcid":true,"given":"Norbert","family":"Str\u00e4ter","sequence":"additional","affiliation":[{"name":"Leipzig University , , ,","place":["Leipzig, Germany, 04103"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0013-6624","authenticated-orcid":true,"given":"Christa E.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"University of Bonn , , An der Immenburg 4 , ,","place":["Bonn, Germany, 53121"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9376-7897","authenticated-orcid":true,"given":"Michael","family":"G\u00fctschow","sequence":"additional","affiliation":[{"name":"University of Bonn , , An der Immenburg 4 , ,","place":["Bonn, Germany, 53121"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,5]]},"reference":[{"key":"2026101511073728500_cit1","doi-asserted-by":"publisher","DOI":"10.1080\/21505594.2025.2480633","article-title":"SARS-CoV-2 epidemiology, kinetics, and evolution: A narrative review","volume":"16","author":"Alizon","year":"2025","journal-title":"Virulence"},{"key":"2026101511073728500_cit2","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1038\/s43856-024-00633-5","article-title":"Morbidity of SARS-CoV-2 in the evolution to endemicity and in comparison with influenza","volume":"4","author":"Bartha","year":"2024","journal-title":"Commun. 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