{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T03:00:05Z","timestamp":1790305205889,"version":"4.1.0"},"reference-count":68,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100024076","name":"Consorcio Interuniversitario do Sistema Universitario de Galicia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100024076","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Proteins"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The severe acute respiratory syndrome coronavirus 2 (SARS\u2010CoV\u20102) continues to evolve and diversify, leading to the emergence of immune\u2010evasive variants and underscoring the need for complementary antiviral strategies targeting conserved viral machinery. In this context, the main protease (Mpro) represents a potential therapeutic target because of its central role in viral replication and its low similarity to human proteases. However, the evolutionary consequences of Mpro variation on substrate recognition and potential resistance remain insufficiently explored. Through the analysis of multiple SARS\u2010CoV\u20102 Mpro variants, we show that, despite ongoing viral diversification, Mpro evolution has remained remarkably constrained since the emergence of the Omicron\u2010associated P132H lineage in 2022, with limited amino\u2010acid substitutions in the active\u2010site and dimerization\u2010interface regions. Across the most prevalent SARS\u2010CoV\u20102 variants, overall substrate recognition by Mpro was largely preserved, although specific variant\u2010substrate pairs exhibited some heterogeneity in per\u2010residue interactions and hydrogen\u2010bond patterns. Ensemble dynamics revealed conserved large\u2010scale motions alongside modest substrate\u2010dependent shifts in secondary motions in certain Mpro variants. Overall, SARS\u2010CoV\u20102 Mpro evolution is strongly constrained by structural and functional requirements, supporting the suitability of this protein as an effective antiviral target. The findings further suggest that incorporating viral evolutionary dynamics may help inform the design of therapeutic strategies with improved long\u2010term robustness.<\/jats:p>","DOI":"10.1002\/prot.70183","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T02:52:02Z","timestamp":1790304722000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Evolution of the\n                    <scp>SARS<\/scp>\n                    \u2010\n                    <scp>CoV<\/scp>\n                    \u20102 Main Protease Under Fitness Constraints Imposed by Folding Stability and Activity"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0757-7702","authenticated-orcid":false,"given":"David","family":"Ferreiro","sequence":"first","affiliation":[{"name":"CINBIO Universidade de Vigo  Vigo Spain"},{"name":"Department of Biochemistry, Genetics and Immunology Universidade de Vigo  Vigo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0516-2717","authenticated-orcid":false,"given":"Miguel","family":"Arenas","sequence":"additional","affiliation":[{"name":"CINBIO Universidade de Vigo  Vigo Spain"},{"name":"Department of Biochemistry, Genetics and Immunology Universidade de Vigo  Vigo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1016\/S0140-6736(21)00947-8","article-title":"Impact and Effectiveness of mRNA BNT162b2 Vaccine Against SARS\u2010CoV\u20102 Infections and COVID\u201019 Cases, Hospitalisations, and Deaths Following a Nationwide Vaccination Campaign in Israel: An Observational Study Using National Surveillance Data","volume":"397","author":"Haas E. 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