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Updated: May 11, 2026
09:59
Functional Reconstitution and Channel Activity Measurements of Purified Wildtype and Mutant CFTR Protein
Published on: March 9, 2015
Mechanism-based corrector combination restores ΔF508-CFTR folding and function
Tsukasa Okiyoneda1, Guido Veit, Johanna F Dekkers
1Department of Physiology, McGill University, Montréal, Quebec, Canada.
Nature Chemical Biology
|May 14, 2013
Summary
Cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-809 shows limited benefit. Stabilizing NBD1 energetics and protein interfaces with multiple correctors may improve ΔF508-CFTR function for cystic fibrosis therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Medical Genetics
Background:
- The common cystic fibrosis mutation ΔF508 in nucleotide binding domain 1 (NBD1) disrupts CFTR folding, expression, and function.
- Current corrector VX-809 has limited clinical efficacy due to an unclear mechanism, hindering drug development.
Purpose of the Study:
- To elucidate the molecular targets of CFTR correctors.
- To identify strategies for robust ΔF508-CFTR correction by stabilizing NBD1 energetics and protein interfaces.
Main Methods:
- Investigated the molecular targets of different classes of CFTR correctors.
- Assessed the efficacy of correctors and chemical chaperones in stabilizing ΔF508-NBD1.
- Evaluated functional plasma membrane expression of ΔF508-CFTR in patient-derived cells and organoids.
Main Results:
- Class I correctors stabilize NBD1-MSD1 and NBD1-MSD2 interfaces; Class II targets NBD2.
- Chemical chaperones stabilize human ΔF508-NBD1, acting as Class III surrogates.
- VX-809 corrects mutations destabilizing the NBD1-MSD1/2 interface, but additional compounds are needed to address NBD1 and NBD2 stability defects.
Conclusions:
- Robust ΔF508-CFTR correction requires addressing both NBD1 energetics and the NBD1-MSD interface defects.
- Combination therapy with structure-guided correctors offers a promising strategy for cystic fibrosis treatment.
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