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Pharmacol."],"abstract":"<jats:sec><jats:title>Background and purpose<\/jats:title><jats:p>The coronavirus disease 2019 (COVID-19) pandemic has devastated global health and the economy, underscoring the urgent need for extensive research into the mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral entry and the development of effective therapeutic interventions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental approach<\/jats:title><jats:p>We established a cell line expressing human angiotensin-converting enzyme 2 (ACE2). We used it as a model of pseudotyped viral entry using murine leukemia virus (MLV) expressing SARS-CoV-2 spike (S) protein on its surface and firefly luciferase as a reporter. We screened an U.S. Food and Drug Administration (FDA)-approved compound library for inhibiting ACE2-dependent SARS-CoV-2 pseudotyped viral entry and identified several drug-repurposing candidates.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key results<\/jats:title><jats:p>We identified 18 drugs and drug candidates, including 14 previously reported inhibitors of viral entry and four novel candidates. Pyridoxal 5\u2032-phosphate, Dovitinib, Adefovir dipivoxil, and Biapenem potently inhibit ACE2-dependent viral entry with inhibitory concentration 50% (IC<jats:sub>50<\/jats:sub>) values of 57nM, 74\u00a0nM, 130\u00a0nM, and 183\u00a0nM, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and implications<\/jats:title><jats:p>We identified four novel FDA-approved candidate drugs for anti-SARS-CoV-2 combination therapy. Our findings contribute to the growing body of evidence supporting drug repurposing as a viable strategy for rapidly developing COVID-19 treatments.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1537912","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T07:19:25Z","timestamp":1742195965000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["FDA-approved drug repurposing screen identifies inhibitors of SARS-CoV-2 pseudovirus entry"],"prefix":"10.3389","volume":"16","author":[{"given":"Manisha","family":"Singh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shruthi","family":"Shanmukha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghda E.","family":"Eldesouki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maged M.","family":"Harraz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"624","DOI":"10.3390\/v15030624","article-title":"Development of next generation vaccines against SARS-CoV-2 and variants of concern","volume":"15","author":"Al-Fattah Yahaya","year":"2023","journal-title":"Viruses"},{"key":"B2","doi-asserted-by":"publisher","first-page":"12364","DOI":"10.33263\/BRIAC114.1236412379","article-title":"Piperaquine- and aspirin- mediated protective role of HSP70 and HSP90 as modes to strengthen the natural immunity against potent SARS-CoV-2","volume":"11","author":"Alreshidi","year":"2021","journal-title":"Biointerface Res. 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