{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:17:10Z","timestamp":1791472630776,"version":"4.3.4"},"reference-count":77,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:00:00Z","timestamp":1760054400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003339","name":"Consejo Superior de Investigaciones Cient\u00edficas","doi-asserted-by":"publisher","award":["CSIC-COV19-110, 202020E254, SGL2103051, 20222AT010"],"award-info":[{"award-number":["CSIC-COV19-110, 202020E254, SGL2103051, 20222AT010"]}],"id":[{"id":"10.13039\/501100003339","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["PID2019-108166GB-I00, PID2022-138917OB-I00"],"award-info":[{"award-number":["PID2019-108166GB-I00, PID2022-138917OB-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006541","name":"Comunidad de Madrid","doi-asserted-by":"publisher","award":["PEJ-2020-TL\/BMD-18670"],"award-info":[{"award-number":["PEJ-2020-TL\/BMD-18670"]}],"id":[{"id":"10.13039\/501100006541","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Respiratory viral infections are a major cause of morbidity and mortality worldwide. The COVID-19 pandemic has evidenced the need for broad-spectrum antivirals and improved preclinical models that more accurately recapitulate human respiratory disease. These new strategies should also involve the search for drug targets in the infected cell that hamper the development of resistance and of potential efficacy against diverse viruses. Since many viruses reprogram cellular metabolism to support viral replication, we performed a comparative analysis of inhibitors targeting the PI3K\/AKT\/mTOR pathway, central to virus-induced metabolic adaptations, using MRC5 lung fibroblasts and Huh7 hepatoma cells. HCoV-229E infection in MRC5 cells caused the expected shift in the energy metabolism but the inhibitors had markedly different effects on the metabolic profile and antiviral activity in these two cell lines. Dichloroacetate (DCA), a clinically approved inhibitor of aerobic glycolysis, showed antiviral activity against HCoV-229E in MRC5 cells, but not in Huh7 cells, underscoring that the screening model is more critical than previously assumed. We further tested DCA in polarized human small airway epithelial cells cultured in air\u2013liquid interface, a 3D model that mimics the human respiratory tract. DCA reduced the viral progeny of HCoV-229E, SARS-CoV-2, and respiratory syncytial virus by 2\u20133 orders of magnitude, even when administered after infection was established. Our work reinforces the need for advanced human preclinical screening models to identify antivirals that target host metabolic pathways frequently hijacked by respiratory viruses, and establishes DCA as a proof-of-concept candidate.<\/jats:p>","DOI":"10.3390\/ijms26209853","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:50:16Z","timestamp":1760107816000},"page":"9853","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Human Small Airway Epithelia Reveal Dichloroacetate as a Broad-Spectrum Antiviral Against Respiratory Viruses"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0401-3134","authenticated-orcid":false,"given":"Paula","family":"Mart\u00ednez de Iturrate","sequence":"first","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margarita Salas, CSIC, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4351-0102","authenticated-orcid":false,"given":"Bruno","family":"Hern\u00e1ez","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa, CSIC-UAM, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4290-5129","authenticated-orcid":false,"given":"Patricia","family":"de los Santos","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margarita Salas, CSIC, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5591-6292","authenticated-orcid":false,"given":"Yolanda","family":"Sierra-Palomares","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margarita Salas, CSIC, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2604-1918","authenticated-orcid":false,"given":"Alba","family":"Garc\u00eda-G\u00f3mez","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margarita Salas, CSIC, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5783-1639","authenticated-orcid":false,"given":"Alonso","family":"S\u00e1nchez-Cruz","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margarita Salas, CSIC, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0846-5019","authenticated-orcid":false,"given":"Catalina","family":"Hern\u00e1ndez-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margarita Salas, CSIC, 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Diabetes y Enfermedades Metab\u00f3licas Asociadas (CIBERDEM-ISCIII), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2958-3233","authenticated-orcid":false,"given":"Luis","family":"Rivas","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margarita Salas, CSIC, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6769-4279","authenticated-orcid":false,"given":"Margarita","family":"del Val","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa, CSIC-UAM, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8634-8902","authenticated-orcid":false,"given":"Eduardo","family":"Rial","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margarita Salas, CSIC, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"104593","DOI":"10.1016\/j.ebiom.2023.104593","article-title":"Viral Respiratory Infections in a Rapidly Changing Climate: The Need to Prepare for the next Pandemic","volume":"93","author":"He","year":"2023","journal-title":"eBioMedicine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S337","DOI":"10.1093\/infdis\/jiad334","article-title":"Report of the Assay Guidance Workshop on 3-Dimensional Tissue Models for Antiviral Drug Development","volume":"228","author":"Jordan","year":"2023","journal-title":"J. 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