{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T14:27:19Z","timestamp":1789050439218,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013981","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000}}],"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T00:00:00Z","timestamp":1771891200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82473844"],"award-info":[{"award-number":["82473844"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018542","name":"Natural Science Foundation of Sichuan Province","doi-asserted-by":"publisher","award":["2026NSFSC0570"],"award-info":[{"award-number":["2026NSFSC0570"]}],"id":[{"id":"10.13039\/501100018542","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the grant of 1.3.5 project, West China Hospital, Sichuan University","award":["ZYYC24004"],"award-info":[{"award-number":["ZYYC24004"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82130104"],"award-info":[{"award-number":["82130104"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Major Project of Guangzhou National Laboratory","award":["GZNL2024A01005"],"award-info":[{"award-number":["GZNL2024A01005"]}]},{"name":"the grant from Frontiers Medical Center, Tianfu Jincheng Laboratory Foundation","award":["TFJCPI20250032"],"award-info":[{"award-number":["TFJCPI20250032"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Swine acute diarrhea syndrome coronavirus (SADS-CoV) poses a significant zoonotic risk. The absence of the structure of SADS-CoV main protease (M\n                    <jats:sup>pro<\/jats:sup>\n                    ) severely impedes the development of effective antiviral therapeutics. Here, we present the high-resolution structures of SADS-CoV M\n                    <jats:sup>pro<\/jats:sup>\n                    and its complexes with inhibitors\n                    <jats:bold>27h<\/jats:bold>\n                    and\n                    <jats:bold>SY110<\/jats:bold>\n                    , respectively. These two compounds inhibit SADS-CoV M\n                    <jats:sup>pro<\/jats:sup>\n                    through a novel inhibition mechanism. Residues 40\u201353 of SADS-CoV M\n                    <jats:sup>pro<\/jats:sup>\n                    adopt a single-helix conformation, in contrast to a coiled coil formed by two consecutive alpha-helices observed in SARS-CoV-2 M\n                    <jats:sup>pro<\/jats:sup>\n                    . These structural differences contribute to the varying inhibitor potency between\n                    <jats:italic>Alphacoronavirus<\/jats:italic>\n                    (\u03b1-CoV) and\n                    <jats:italic>Betacoronavirus<\/jats:italic>\n                    (\u03b2-CoV) M\n                    <jats:sup>pro<\/jats:sup>\n                    s. We subsequently demonstrate that the absence of residue \u201851\u2019 in \u03b1-CoV M\n                    <jats:sup>pro<\/jats:sup>\n                    s plays a key role in these conformational changes. Furthermore,\n                    <jats:bold>27h<\/jats:bold>\n                    was proved to efficiently suppress SADS-CoV replication in both cell-based assays and porcine intestinal organoids\u2014marking the first such assessment. Overall, these findings reveal that intrinsic M\n                    <jats:sup>pro<\/jats:sup>\n                    dynamics influence inhibitor potency and provide insights for designing broad-spectrum M\n                    <jats:sup>pro<\/jats:sup>\n                    inhibitors.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1013981","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T18:39:52Z","timestamp":1771958392000},"page":"e1013981","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["An intrinsic loop-mediated structural stability modulating inhibitor potency in the SADS-CoV and SARS-CoV-2 main 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