{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T11:30:31Z","timestamp":1781350231615,"version":"3.54.1"},"reference-count":117,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP22K15284"],"award-info":[{"award-number":["JP22K15284"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["21fk0108568h0001"],"award-info":[{"award-number":["21fk0108568h0001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The COVID-19 pandemic, caused by SARS-CoV-2, has profoundly affected global health and the economy. The emergence of variants with spike mutations, particularly within the receptor-binding domain (RBD), has reduced the efficacy of many neutralizing antibodies (nAbs), and recent variants, including KP.3 and other circulating strains, show partial escape from infection- or vaccine-induced immunity. To overcome this, developing broad-spectrum nAbs that target the conserved S2 subunit of the spike protein is crucial. Unlike the highly mutable RBD, the S2 region remains structurally conserved, providing a promising foundation for universal protection. Deeper insight into S2 structure and function, together with advances in bispecific antibody design, could facilitate the development of next-generation therapeutics resilient to viral evolution. This review examines the structural evolution of the SARS-CoV-2 spike, focusing on the therapeutic potential of S2-targeting antibodies and strategies to overcome antibody resistance.<\/jats:p>","DOI":"10.3390\/biom15111489","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T01:14:02Z","timestamp":1761182042000},"page":"1489","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Structural Insights into the SARS-CoV-2 Spike Protein and Its Implications for Antibody Resistance"],"prefix":"10.3390","volume":"15","author":[{"given":"Yuichiro","family":"Yamamoto","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Targeted Therapy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1, Niijuku, Katsushika-ku, Tokyo 125-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9080-0807","authenticated-orcid":false,"given":"Kohji","family":"Noguchi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Targeted Therapy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1, Niijuku, Katsushika-ku, Tokyo 125-8585, Japan"},{"name":"Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Japan Institute for Health Security, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1016\/j.it.2020.10.004","article-title":"Mechanisms of SARS-CoV-2 Transmission and Pathogenesis","volume":"41","author":"Harrison","year":"2020","journal-title":"Trends Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41579-022-00713-0","article-title":"SARS-CoV-2 Pathogenesis","volume":"20","author":"Lamers","year":"2022","journal-title":"Nat. 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