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In co-crystal structures of M\n                    <jats:sup>pro<\/jats:sup>\n                    of SARS-CoV-2 with peptidomimetic inhibitors, we noticed a spatial proximity of sidechains filling the S1\u2019 and S2 pockets, as well as those filling S3 and S1 pockets. To enhance molecular rigidity, the proximal residues were conformationally fixed by macrocyclization. We report the synthesis of two macrocyclic series, i.e. exocyclic nitriles with linked P3 and P1 residues and endocyclic \u03b1-ketoamides with linked P1\u2019 and P2 residues, and characterize their binding modes and bioactivities. The 17-membered macrocyclic \u03b1-ketoamide\n                    <jats:bold>20\u2009f<\/jats:bold>\n                    inhibited M\n                    <jats:sup>pro<\/jats:sup>\n                    (IC\u2085\u2080 = 370\u2009nM) and exerted anti-SARS-CoV-2 effects (EC\u2085\u2080 = 1.9\u2009\u03bcM). Leveraging structural similarities between M\n                    <jats:sup>pro<\/jats:sup>\n                    and the 3C\n                    <jats:sup>pro<\/jats:sup>\n                    of enterovirus D68, we describe with two co-crystal structures how \u03b1-ketoamide macrocycles bound to and inhibited the enteroviral protease. Notably,\n                    <jats:bold>20\u2009f<\/jats:bold>\n                    exhibited very potent antiviral activities with EC\u2085\u2080\u2018s of 33, 133, and 146\u2009nM against EV-D68, EV-A71, and CVB3, respectively. The study demonstrates how broad-spectrum activity can be achieved with direct-acting antivirals.\n                  <\/jats:p>","DOI":"10.1038\/s42004-026-02151-y","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T15:53:35Z","timestamp":1786031615000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structure-based macrocyclization of \u03b1-ketoamides leads to potent inhibitors of coronaviral and enteroviral proteases"],"prefix":"10.1038","volume":"9","author":[{"given":"Ravi Kumar","family":"Akula","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4084-3582","authenticated-orcid":false,"given":"Haifa","family":"El Kilani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Metzen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjata","family":"Joshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilal","family":"Durmaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Veenstra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7776-9729","authenticated-orcid":false,"given":"Judith","family":"R\u00f6ske","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3834-5808","authenticated-orcid":false,"given":"Daniel L.","family":"Hurdiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank J. 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