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Despite vaccine availability, continuous emergence of viral variants with enhanced transmissibility and immune escape capabilities, and consequential impacts on health services, requires effective antiviral therapeutics. Drug repurposing offers an expeditious strategy to identify therapeutics with established safety profiles. We implemented a comprehensive three\u2010tiered validation approach, screening 2,570 compounds against SARS\u2010CoV\u20102 in vitro, followed by\n                    <jats:italic>ex vivo<\/jats:italic>\n                    validation in well\u2010differentiated primary human bronchial epithelial cell (WD\u2010PBEC) cultures, and rigorous in vivo assessment. This methodical progression identified Azatadine\u2010Dimaleate, a H1\u2010receptor antagonist, as an exceptional candidate with consistent efficacy across all systems. Azatadine\u2010Dimaleate demonstrated potent antiviral activity\u2010 EC50: 4.0\u2009\u00b5M (95% CI: 3.2\u20134.8\u2009\u00b5M), reducing viral replication by ~5,000\u2010fold at 25\u2009\u00b5M in epithelial cultures and lowering peak viral titers in WD\u2010PBECs by 1.4 log\n                    <jats:sub>10<\/jats:sub>\n                    , and 2.33 log\n                    <jats:sub>10<\/jats:sub>\n                    at 48 and 96 hpi, respectively, compared to controls. There was also a concomitant reduction in expression of interferons and pro\u2010inflammatory genes, including IL\u20106. Combination with Remdesivir synergistically enhanced antiviral activity, reducing the EC50 of both drugs by &gt;\u200960%. In the K18\u2010hACE2 transgenic mouse model, Azatadine\u2010Dimaleate significantly reduced weight loss (4%\n                    <jats:italic>vs.<\/jats:italic>\n                    12%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009\u2264\u20090.05), decreased viral loads, and halved viral antigen expression in lung tissues. Unlike many candidates that faltered in complex models, Azatadine\u2010Dimaleate maintained efficacy across all platforms. These findings support its clinical evaluation, alone or in combination with Remdesivir, as a versatile therapeutic with strong potential to address current and emerging SARS\u2010CoV\u20102 variants.\n                  <\/jats:p>","DOI":"10.1002\/jmv.70713","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T10:38:22Z","timestamp":1763635102000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Preclinical Screening Platform Identifies Azatadine\u2010Dimaleate as a Potent Repurposed Therapeutic Against SARS\u2010CoV\u20102 Infection"],"prefix":"10.1002","volume":"97","author":[{"given":"Ahlam","family":"Ali","sequence":"first","affiliation":[{"name":"Patrick G Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Sciences Queen's University Belfast; Belfast Belfast Ireland"},{"name":"Current Affiliation: School of Life Sciences University of Wolverhampton Wolverhampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Courtney","sequence":"additional","affiliation":[{"name":"Wellcome\u2010Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences Queen's University Belfast; Belfast Belfast Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay","family":"Broadbent","sequence":"additional","affiliation":[{"name":"Wellcome\u2010Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences Queen's University Belfast; Belfast Belfast Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parul","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Infection Biology and Microbiomes University of Liverpool Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connor G. 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