{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T09:28:31Z","timestamp":1771752511905,"version":"3.50.1"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,4,11]],"date-time":"2024-04-11T00:00:00Z","timestamp":1712793600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18H03334 21H00294 22H02576"],"award-info":[{"award-number":["18H03334 21H00294 22H02576"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012044","name":"Kwansei Gakuin University","doi-asserted-by":"publisher","award":["Individual Special Research Subsidy with grants"],"award-info":[{"award-number":["Individual Special Research Subsidy with grants"]}],"id":[{"id":"10.13039\/100012044","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Cystic fibrosis (CF) is a monogenetic disease caused by the mutation of CFTR, a cAMP-regulated Cl<jats:sup>\u2212<\/jats:sup> channel expressing at the apical plasma membrane (PM) of epithelia. \u2206F508-CFTR, the most common mutant in CF, fails to reach the PM due to its misfolding and premature degradation at the endoplasmic reticulum (ER). Recently, CFTR modulators have been developed to correct CFTR abnormalities, with some being used as therapeutic agents for CF treatment. One notable example is Trikafta, a triple combination of CFTR modulators (TEZ\/ELX\/IVA), which significantly enhances the functionality of \u0394F508-CFTR on the PM. However, there\u2019s room for improvement in its therapeutic effectiveness since TEZ\/ELX\/IVA doesn't fully stabilize \u0394F508-CFTR on the PM. To discover new CFTR modulators, we conducted a virtual screening of approximately 4.3 million compounds based on the chemical structures of existing CFTR modulators. This effort led us to identify a novel CFTR ligand named FR3. Unlike clinically available CFTR modulators, FR3 appears to operate through a distinct mechanism of action. FR3 enhances the functional expression of \u0394F508-CFTR on the apical PM in airway epithelial cell lines by stabilizing NBD1. Notably, FR3 counteracted the degradation of mature \u0394F508-CFTR, which still occurs despite the presence of TEZ\/ELX\/IVA. Furthermore, FR3 corrected the defective PM expression of a misfolded ABCB1 mutant. Therefore, FR3 may be a potential lead compound for addressing diseases resulting from the misfolding of ABC transporters.<\/jats:p>","DOI":"10.3389\/fphar.2024.1370676","type":"journal-article","created":{"date-parts":[[2024,4,11]],"date-time":"2024-04-11T04:24:31Z","timestamp":1712809471000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Ligand-based virtual-screening identified a novel CFTR ligand which improves the defective cell surface expression of misfolded ABC transporters"],"prefix":"10.3389","volume":"15","author":[{"given":"Shogo","family":"Taniguchi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francois","family":"Berenger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukako","family":"Doi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayana","family":"Mimura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshihiro","family":"Yamanishi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsukasa","family":"Okiyoneda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,4,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3787","DOI":"10.1091\/mbc.E13-07-0417","article-title":"Ubiquitination-dependent quality control of hERG K+ channel with acquired and inherited conformational defect at the plasma membrane","volume":"24","author":"Apaja","year":"2013","journal-title":"Mol. 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