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dc.contributor.authorVeit, G
dc.contributor.authorRoldan, A
dc.contributor.authorHancock, MA
dc.contributor.authorDa Fonte, DF
dc.contributor.authorXu, H
dc.contributor.authorHussein, M
dc.contributor.authorFrenkiel, S
dc.contributor.authorMatouk, E
dc.contributor.authorVelkov, T
dc.contributor.authorLukacs, GL
dc.date.accessioned2020-11-17T03:51:13Z
dc.date.available2020-11-17T03:51:13Z
dc.date.issued2020-09-17
dc.identifierpii: 139983
dc.identifier.citationVeit, G., Roldan, A., Hancock, M. A., Da Fonte, D. F., Xu, H., Hussein, M., Frenkiel, S., Matouk, E., Velkov, T. & Lukacs, G. L. (2020). Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination. JCI INSIGHT, 5 (18), https://doi.org/10.1172/jci.insight.139983.
dc.identifier.issn2379-3708
dc.identifier.urihttp://hdl.handle.net/11343/251618
dc.description.abstractBased on its clinical benefits, Trikafta - the combination of folding correctors VX-661 (tezacaftor), VX-445 (elexacaftor), and the gating potentiator VX-770 (ivacaftor) - was FDA approved for treatment of patients with cystic fibrosis (CF) carrying deletion of phenylalanine at position 508 (F508del) of the CF transmembrane conductance regulator (CFTR) on at least 1 allele. Neither the mechanism of action of VX-445 nor the susceptibility of rare CF folding mutants to Trikafta are known. Here, we show that, in human bronchial epithelial cells, VX-445 synergistically restores F508del-CFTR processing in combination with type I or II correctors that target the nucleotide binding domain 1 (NBD1) membrane spanning domains (MSDs) interface and NBD2, respectively, consistent with a type III corrector mechanism. This inference was supported by the VX-445 binding to and unfolding suppression of the isolated F508del-NBD1 of CFTR. The VX-661 plus VX-445 treatment restored F508del-CFTR chloride channel function in the presence of VX-770 to approximately 62% of WT CFTR in homozygous nasal epithelia. Substantial rescue of rare misprocessing mutations (S13F, R31C, G85E, E92K, V520F, M1101K, and N1303K), confined to MSD1, MSD2, NBD1, and NBD2 of CFTR, was also observed in airway epithelia, suggesting an allosteric correction mechanism and the possible application of Trikafta for patients with rare misfolding mutants of CFTR.
dc.languageEnglish
dc.publisherAMER SOC CLINICAL INVESTIGATION INC
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleAllosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination
dc.typeJournal Article
dc.identifier.doi10.1172/jci.insight.139983
melbourne.affiliation.departmentPharmacology and Therapeutics
melbourne.source.titleJCI Insight
melbourne.source.volume5
melbourne.source.issue18
dc.rights.licenseCC BY
melbourne.elementsid1466302
melbourne.contributor.authorVelkov, Tony
melbourne.contributor.authorHussein, Maytham
dc.identifier.eissn2379-3708
melbourne.accessrightsOpen Access


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