{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T23:45:40Z","timestamp":1783467940825,"version":"3.55.0"},"reference-count":63,"publisher":"National Academy of Sciences","issue":"5","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000292","name":"Cystic Fibrosis Trust","doi-asserted-by":"publisher","award":["SRC 021"],"award-info":[{"award-number":["SRC 021"]}],"id":[{"id":"10.13039\/501100000292","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,2,3]]},"abstract":"<jats:p>\n                    Elexacaftor-tezacaftor-ivacaftor has transformed the treatment of people with cystic fibrosis (CF) and the predominant cystic fibrosis transmembrane conductance regulator (\n                    <jats:italic toggle=\"yes\">CFTR<\/jats:italic>\n                    ) variant F508del by delivering the faulty channel to the plasma membrane and potentiating its activity. However, the action of elexacaftor-tezacaftor-ivacaftor on the molecular behavior of F508del-CFTR is unknown. Here, we investigated the impact of elexacaftor-tezacaftor-ivacaftor on individual human F508del-CFTR Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    channels using the patch-clamp technique and cells heterologously expressing F508del-CFTR. Chronic treatment of F508del-CFTR-expressing cells with elexacaftor-tezacaftor-ivacaftor, but not pairs of CFTR modulators, stabilized F508del-CFTR, preventing channel deactivation in cell-free membrane patches and conferring upon it the current amplitude of wild-type CFTR with channel activity sustained at a level one-third that of wild-type CFTR. By incubating cells with different drug concentrations, we demonstrated that elexacaftor stabilizes the open-channel conformation of elexacaftor-tezacaftor-ivacaftor-rescued F508del-CFTR, while acute treatment of wild-type CFTR with elexacaftor increased current flow through the channel and potentiated channel gating. Of note, acute treatment of elexacaftor-tezacaftor-ivacaftor-rescued F508del-CFTR Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    channels with elexacaftor and ivacaftor restored wild-type levels of channel activity to the\n                    <jats:italic toggle=\"yes\">CFTR<\/jats:italic>\n                    variant, albeit its gating pattern was distinct from that of wild-type CFTR and characterized by infrequent prolonged bursts of channel openings. In conclusion, chronic treatment with elexacaftor-tezacaftor-ivacaftor plus acute treatment with elexacaftor and ivacaftor robustly corrects the processing, stability, and gating defects of F508del-CFTR. Our results reveal that elexacaftor is a triple-acting CFTR modulator with corrector, potentiator, and conduction activities, making it a valuable therapeutic to rescue\n                    <jats:italic toggle=\"yes\">CFTR<\/jats:italic>\n                    variants with distinct molecular mechanisms of CFTR dysfunction.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2523950123","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T18:51:15Z","timestamp":1769194275000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":3,"title":["Chronic and acute modulator treatment restore wild-type-like activity and stability to the primary cystic fibrosis\u2013causing\n                    <i>CFTR<\/i>\n                    variant"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2062-8682","authenticated-orcid":false,"given":"Mayuree","family":"Rodrat","sequence":"first","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience, University of Bristol","place":["Bristol, United Kingdom"]},{"name":"Center for Advanced Therapeutics, Institute of Molecular Biosciences, Mahidol University","place":["Nakhon Pathom, Thailand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9798-7769","authenticated-orcid":false,"given":"James N.","family":"Charlick","sequence":"additional","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience, University of Bristol","place":["Bristol, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5533-9130","authenticated-orcid":false,"given":"David N.","family":"Sheppard","sequence":"additional","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience, University of Bristol","place":["Bristol, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)32597-8"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1908639"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2475911"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90148-8"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/358761a0"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb882"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.ade2216"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/354526a0"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(20)80582-1"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1300109"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201711946"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/164_2022_597"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0904709106"},{"key":"e_1_3_4_14_2","first-page":"274","article-title":"Nonclinical profile of the CFTR corrector VX-661","volume":"45","author":"Van Goor F.","year":"2016","unstructured":"F. 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Sheppard M. Rodrat J. Charlick Data from \u201cChronic and acute modulator treatment restore wild-type-like activity and stability to the primary cystic fibrosis-causing variant.\u201d data.bris. https:\/\/doi.org\/10.5523\/bris.md1upto2lx8x2u1iu64x2k9sz. Deposited 5 December 2025."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2523950123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T18:51:18Z","timestamp":1769194278000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2523950123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,23]]},"references-count":63,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,2,3]]}},"alternative-id":["10.1073\/pnas.2523950123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2523950123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,23]]},"assertion":[{"value":"2025-08-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2523950123"}}