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To date, a few primary human stem cell-based models of the proximal airway have been reported for drug discovery but scaling them up to a higher throughput platform remains a significant challenge. As a result, most of the drug screening assays for respiratory viruses are performed on commercial cell line-based 2D cultures that provide limited translational ability.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We optimized a primary human stem cell-based mucociliary airway epithelium model of SARS-CoV-2 infection, in 96-well air\u2013liquid-interface (ALI) format, which is amenable to moderate throughput drug screening. We tested the model against SARS-CoV-2 parental strain (Wuhan) and variants Beta, Delta, and Omicron. We applied this model to screen 2100 compounds from targeted drug libraries using a high throughput-high content image-based quantification method.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>The model recapitulated the heterogeneity of infection among patients with SARS-CoV-2 parental strain and variants. While there were heterogeneous responses across variants for host factor targeting compounds, the two direct-acting antivirals we tested, Remdesivir and Paxlovid, showed consistent efficacy in reducing infection across all variants and donors. Using the model, we characterized a new antiviral drug effective against both the parental strain and the Omicron variant.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>This study demonstrates that the 96-well ALI model of primary human mucociliary epithelium can recapitulate the heterogeneity of infection among different donors and SARS-CoV-2 variants and can be used for moderate throughput screening. Compounds that target host factors showed variability among patients in response to SARS-CoV-2, while direct-acting antivirals were effective against SARS-CoV-2 despite the heterogeneity of patients tested.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s12931-025-03095-y","type":"journal-article","created":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T17:54:56Z","timestamp":1737050096000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Optimization of a micro-scale air\u2013liquid-interface model of human proximal airway epithelium for moderate throughput drug screening for SARS-CoV-2"],"prefix":"10.1186","volume":"26","author":[{"given":"Chandani","family":"Sen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammy M.","family":"Rickabaugh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjit Vijey","family":"Jeyachandran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constance","family":"Yuen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maisam","family":"Ghannam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdo","family":"Durra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Aziz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Castillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Gustavo","family":"Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arunima","family":"Purkayastha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix W.","family":"Boulton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene","family":"Chekler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Garces","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen C.","family":"Wolff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Riva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie G.","family":"Kirkpatrick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amal","family":"Gebara-Lamb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Case W.","family":"McNamara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich A. 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All patient samples used in this study were de-identified and were collected with an Institutional Review Board (IRB) exemption. The need for consent was waived by the IRB. Patient large airways and bronchial tissues were acquired from three different tissue sources: 1. de-identified normal human donors after lung transplantations at the Ronald Reagan UCLA Medical Center. Tissues were procured under an Institutional Review Board-approved protocol at the David Geffen School of Medicine at UCLA (IRB#21-000390-CR-00003). 2. Normal human bronchial epithelial cells (NHBE) from non-smokers were obtained from Lonza and all samples were de-identified. 3. Deidentified donor lung and trachea samples from the International Institute for the Advancement of Medicine (IIAM) were obtained with institutional approval. All animal studies were carried out according to the standard operating procedure in place at the test facility at Vibiosphen. All procedures were performed in accordance with the Directive 2010\/63\/UE recommendations and with French Veterinary Authorities agreement. All animals were managed similarly, with due regard for their well-being, according to prevailing practices and the current SOPs in force at Vibiosphen. The\u00a0in vivo\u00a0design and procedures were approved by Ethical Committee.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical Approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Ulrich AK Betz, Eugene Chekler, and Robert Garces are or were employees of Merck KGaA, Darmstadt, Germany, or its affiliated companies and there is a patent application associated with this work. Brigitte Gomperts is a co-founder and consultant for InSpira LLC. Other authors declare no competing financial interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"18"}}