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Emerging SARS-CoV-2 variants are a roadblock to irradicating the disease. Given recombinant human annexin A5 (Anx5) inhibits proinflammatory responses, improves survival in sepsis models and binds to several receptors and lipids, we hypothesized that Anx5 impedes SARS-CoV-2 viral entry and lessens disease severity. To assess SARS-CoV-2 Spike-receptor binding domain (RBD) and ACE2 interactions with Anx5, the recombinant proteins were expressed and isolated, and interactions were evaluated using solution NMR, microscale thermophoresis, steady-state fluorescence and size-exclusion chromatography coupled to multi-angle light scattering. Remarkably, we found that Anx5 binds to both the Spike-RBD and ACE2. Further, Anx5 induced extensive\n                    <jats:sup>15<\/jats:sup>\n                    N-Spike-RBD amide resonance broadening, most concentrated in the region that engages with ACE2 and least enriched on the opposite face, highlighting the ACE2 interface as the primary site of Anx5 binding. Finally, we demonstrate that Anx5 inhibits SARS-CoV-2 pseudoviral entry and reduces viral burden while enhancing survival in SARS-CoV-2-infected mammalian cells. Collectively, our findings demonstrate that Anx5 directly engages both Spike-RBD and ACE2, inhibits SARS-CoV-2 pseudoviral entry and reduces viral burden while enhancing survival of infected mammalian cells, supporting further investigation of Anx5 as a multi-functional anti-SARS-CoV-2 therapeutic.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-58451-9","type":"journal-article","created":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T04:04:25Z","timestamp":1781928265000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual engagement of Spike and ACE2 by annexin A5 contributes to pleiotropic SARS-CoV-2 inhibition"],"prefix":"10.1038","volume":"16","author":[{"given":"Arundhasa","family":"Chandrabalan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi-Tong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khandaker Atkia","family":"Fariha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Solis-Reyes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connor G.","family":"Richer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan M.","family":"Troyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen D.","family":"Barr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingping","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0536-6656","authenticated-orcid":false,"given":"Peter B.","family":"Stathopulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,20]]},"reference":[{"key":"58451_CR1","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1038\/s41579-022-00841-7","volume":"21","author":"AM Carabelli","year":"2023","unstructured":"Carabelli, A. M. et al. SARS-CoV-2 variant biology: immune escape, transmission and fitness. Nat. Rev. Microbiol. 21, 162\u2013177. https:\/\/doi.org\/10.1038\/s41579-022-00841-7 (2023).","journal-title":"Nat. Rev. Microbiol."},{"key":"58451_CR2","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/s41586-020-2012-7","volume":"579","author":"P Zhou","year":"2020","unstructured":"Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270\u2013273. https:\/\/doi.org\/10.1038\/s41586-020-2012-7 (2020).","journal-title":"Nature"},{"key":"58451_CR3","doi-asserted-by":"publisher","DOI":"10.1101\/2020.06.22.165803","author":"R Amraei","year":"2021","unstructured":"Amraei, R. et al. 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The remaining authors have disclosed that they do not have any potential conflicts of interest.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"COVID-19 patient serum use was approved by Western University REB. Western University REB operates in compliance with, and is constituted in accordance with, the requirements of the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS 2); the International Conference on Harmonisation Good Clinical Practice Consolidated Guideline (ICH GCP); Part C, Division 5 of the Food and Drug Regulations; Part 4 of the Natural Health Products Regulations; Part 3 of the Medical Devices Regulations and the provisions of the Ontario Personal Health Information Protection Act (PHIPA 2004) and its applicable regulations. The REB is registered with the U.S. Department of Health & Human Services under the IRB registration number IRB 00000940. Project ID: 115793, Study Title: In-vitro Analyses of the 2019 novel coronavirus SARS-CoV-2 circulating in London, Ontario for the betterment of drug and vaccine development and to understand CoV-2 pathogenesis Application Type: Continuing Ethics Review (CER) Form. The research has been carried out in accordance with the World Medical Association Declaration of Helsinki, and all subjects have provided written informed consent.","order":2,"name":"Ethics","label":"Ethics statement","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"28261"}}