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A prominent component of COVID-19 is the infection and destruction of the ciliated respiratory cells, which perpetuates dissemination and disrupts protective mucociliary transport (MCT) function, an innate defense of the respiratory tract. Thus, drugs that augment MCT could improve the barrier function of the airway epithelium and reduce viral replication and, ultimately, COVID-19 outcomes. We tested five agents known to increase MCT through distinct mechanisms for activity against SARS-CoV-2 infection using a model of human respiratory epithelial cells terminally differentiated in an air\/liquid interphase. Three of the five mucoactive compounds tested showed significant inhibitory activity against SARS-CoV-2 replication. An archetype mucoactive agent, ARINA-1, blocked viral replication and therefore epithelial cell injury; thus, it was further studied using biochemical, genetic, and biophysical methods to ascertain the mechanism of action via the improvement of MCT. ARINA-1 antiviral activity was dependent on enhancing the MCT cellular response, since terminal differentiation, intact ciliary expression, and motion were required for ARINA-1-mediated anti-SARS-CoV2 protection. Ultimately, we showed that the improvement of cilia movement was caused by ARINA-1-mediated regulation of the redox state of the intracellular environment, which benefited MCT. Our study indicates that intact MCT reduces SARS-CoV-2 infection, and its pharmacologic activation may be effective as an anti-COVID-19 treatment. <\/jats:p>","DOI":"10.1152\/ajplung.00285.2022","type":"journal-article","created":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T16:02:27Z","timestamp":1676995347000},"page":"L493-L506","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Mucociliary clearance augmenting drugs block SARS-CoV-2 replication in human airway epithelial cells"],"prefix":"10.1152","volume":"324","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2693-0885","authenticated-orcid":false,"given":"Javier","family":"Campos-G\u00f3mez","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Alabama at Birmingham, Alabama, United States"},{"name":"Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Alabama, United 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