CFTR correctors potentiate gating mutants causing cystic fibrosis
Abstract
The Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulator VX-445 (Elexacaftor) used to treat cystic fibrosis presents both corrector and potentiator activities. This drug binds to a pocket within the CFTR membrane-spanning domain (MSD) assembly, in contact with the lasso motif. We have previously shown that the corrector activity of VX-445 is modulated by mutations within MSD1 and the nucleotide binding domain NBD1. Here, we evaluate if mutations affecting VX-445's corrector activity also affect its potentiator activity. Responses to increasing concentrations of VX-445 were measured using the halide sensitive fluorescent assay after transfection of CFTR mutants in HEK293 cells. Results show that VX-445 potentiated gating mutants causing cystic fibrosis located in the NBDs (NBD1 G551D and NBD2 G1349D) and in the IntraCellular Loops (ICL1 G178R and ICL3 G970R). Mutations within the VX-445 binding site inhibited potentiation of G551D, contrary to some mutations located outside this site that affected its corrector activity, two of which (M212A and F224A) were found to induce CFTR gain-of-function. Potentiation of G551D was also observed with correctors VX-809 and VX-121. In conclusion, CFTR modulator VX-445 can promote channel activity of gating mutants, an effect which is dependent on the integrity of its binding site. Potentiation could also be observed with correctors VX-809 and VX-121, indicating that more generally, CFTR correctors can promote channel activity.
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BibTeX
@article{castanier2026cftr,
title = {{CFTR correctors potentiate gating mutants causing cystic fibrosis}},
author = {Solène Castanier and Ahmad Elbahnsi and Benoit Chevalier and Lynda Berri and Madara Dias Wickramanayaka and Jean-Paul Mornon and Aurélie Hatton and Isabelle Sermet-Gaudelus and Aleksander Edelman and Isabelle Callebaut and Alexandre Hinzpeter},
journal = {Journal of Cystic Fibrosis},
year = {2026},
month = oct,
doi = {10.1016/j.jcf.2025.11.008},
url = {https://hal.science/hal-05820536v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - CFTR correctors potentiate gating mutants causing cystic fibrosis
AU - Solène Castanier
AU - Ahmad Elbahnsi
AU - Benoit Chevalier
AU - Lynda Berri
AU - Madara Dias Wickramanayaka
AU - Jean-Paul Mornon
AU - Aurélie Hatton
AU - Isabelle Sermet-Gaudelus
AU - Aleksander Edelman
AU - Isabelle Callebaut
AU - Alexandre Hinzpeter
PY - 2026
DA - 2026/10/20
JO - Journal of Cystic Fibrosis
DO - 10.1016/j.jcf.2025.11.008
UR - https://hal.science/hal-05820536v1
AB - The Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulator VX-445 (Elexacaftor) used to treat cystic fibrosis presents both corrector and potentiator activities. This drug binds to a pocket within the CFTR membrane-spanning domain (MSD) assembly, in contact with the lasso motif. We have previously shown that the corrector activity of VX-445 is modulated by mutations within MSD1 and the nucleotide binding domain NBD1. Here, we evaluate if mutations affecting VX-445's corrector activity also affect its potentiator activity. Responses to increasing concentrations of VX-445 were measured using the halide sensitive fluorescent assay after transfection of CFTR mutants in HEK293 cells. Results show that VX-445 potentiated gating mutants causing cystic fibrosis located in the NBDs (NBD1 G551D and NBD2 G1349D) and in the IntraCellular Loops (ICL1 G178R and ICL3 G970R). Mutations within the VX-445 binding site inhibited potentiation of G551D, contrary to some mutations located outside this site that affected its corrector activity, two of which (M212A and F224A) were found to induce CFTR gain-of-function. Potentiation of G551D was also observed with correctors VX-809 and VX-121. In conclusion, CFTR modulator VX-445 can promote channel activity of gating mutants, an effect which is dependent on the integrity of its binding site. Potentiation could also be observed with correctors VX-809 and VX-121, indicating that more generally, CFTR correctors can promote channel activity.
SN - 1569-1993
SN - 1873-5010
ER -