{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T00:46:50Z","timestamp":1768783610442,"version":"3.49.0"},"reference-count":62,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T00:00:00Z","timestamp":1701993600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Cystic Fibrosis Research Foundation","award":["FFC#3\/2018"],"award-info":[{"award-number":["FFC#3\/2018"]}]},{"name":"Italian Cystic Fibrosis Research Foundation","award":["FFC#9\/2021"],"award-info":[{"award-number":["FFC#9\/2021"]}]},{"name":"Italian Cystic Fibrosis Research Foundation","award":["FRA2022"],"award-info":[{"award-number":["FRA2022"]}]},{"DOI":"10.13039\/501100004702","name":"University of Genoa","doi-asserted-by":"publisher","award":["FFC#3\/2018"],"award-info":[{"award-number":["FFC#3\/2018"]}],"id":[{"id":"10.13039\/501100004702","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004702","name":"University of Genoa","doi-asserted-by":"publisher","award":["FFC#9\/2021"],"award-info":[{"award-number":["FFC#9\/2021"]}],"id":[{"id":"10.13039\/501100004702","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004702","name":"University of Genoa","doi-asserted-by":"publisher","award":["FRA2022"],"award-info":[{"award-number":["FRA2022"]}],"id":[{"id":"10.13039\/501100004702","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Cystic fibrosis (CF), the most common autosomal recessive fatal genetic disease in the Caucasian population, is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel that regulates salt and water transport across a variety of secretory epithelia. Deletion of phenylalanine at position 508, F508del, the most common CF-causing mutation, destabilises the CFTR protein, causing folding and trafficking defects that lead to a dramatic reduction in its functional expression. Small molecules called correctors have been developed to rescue processing-defective F508del CFTR. We have combined in silico and in vitro approaches to investigate the mechanism of action and potential as CFTR correctors of three hybrid derivatives (2a, 7a, and 7m) obtained by merging the amino-arylthiazole core with the benzodioxole carboxamide moiety characterising the corrector lumacaftor. Molecular modelling analyses suggested that the three hybrids interact with a putative region located at the MSD1\/NBD1 interface. Biochemical analyses confirmed these results, showing that the three molecules affect the expression and stability of the F508del NBD1. Finally, the YFP assay was used to evaluate the influence of the three hybrid derivatives on F508del CFTR function, assessing that their effect is additive to that of the correctors VX661 and VX445. Our study shows that the development and testing of optimised compounds targeting different structural and functional defects of mutant CFTR is the best strategy to provide more effective correctors that could be used alone or in combination as a valuable therapeutic option to treat an even larger cohort of people affected by CF.<\/jats:p>","DOI":"10.3390\/ph16121702","type":"journal-article","created":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T05:47:30Z","timestamp":1702014450000},"page":"1702","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["In Silico and In Vitro Evaluation of the Mechanism of Action of Three VX809-Based Hybrid Derivatives as Correctors of the F508del CFTR Protein"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8764-2468","authenticated-orcid":false,"given":"Debora","family":"Baroni","sequence":"first","affiliation":[{"name":"Istituto di Biofisica, Consiglio Nazionale delle Ricerche (CNR), Via De Marini, 6, 16149 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5121-715X","authenticated-orcid":false,"given":"Naomi","family":"Scarano","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genova, Viale Benedetto XV, 3, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Ludovico","sequence":"additional","affiliation":[{"name":"Istituto di Biofisica, Consiglio Nazionale delle Ricerche (CNR), Via De Marini, 6, 16149 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1548-6720","authenticated-orcid":false,"given":"Chiara","family":"Brandas","sequence":"additional","affiliation":[{"name":"Istituto di Biofisica, Consiglio Nazionale delle Ricerche (CNR), Via De Marini, 6, 16149 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alice","family":"Parodi","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dario","family":"Lunaccio","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9386-0445","authenticated-orcid":false,"given":"Paola","family":"Fossa","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genova, Viale Benedetto XV, 3, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1287-6176","authenticated-orcid":false,"given":"Oscar","family":"Moran","sequence":"additional","affiliation":[{"name":"Istituto di Biofisica, Consiglio Nazionale delle Ricerche (CNR), Via De Marini, 6, 16149 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Cichero","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genova, Viale Benedetto XV, 3, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4019-0051","authenticated-orcid":false,"given":"Enrico","family":"Millo","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1126\/science.2475911","article-title":"Identification of the Cystic Fibrosis Gene: Cloning and Characterization of Complementary DNA","volume":"245","author":"Riordan","year":"1989","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1126\/science.2570460","article-title":"Identification of the Cystic Fibrosis Gene: Genetic Analysis","volume":"245","author":"Kerem","year":"1989","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s00018-016-2393-9","article-title":"Cystic Fibrosis: A Clinical View","volume":"74","author":"Castellani","year":"2017","journal-title":"Cell. 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