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Mechanism-based corrector combination restores DeltaF508-CFTR folding and function Okiyoneda T; Veit G; Dekkers JF; Bagdany M; Soya N; Xu H; Roldan A; Verkman AS; Kurth M; Simon A; Hegedus T; Beekman JM; Lukacs GLNat Chem Biol 2013[Jul]; 9 (7): 444-54The most common cystic fibrosis mutation, DeltaF508 in nucleotide binding domain 1 (NBD1), impairs cystic fibrosis transmembrane conductance regulator (CFTR)-coupled domain folding, plasma membrane expression, function and stability. VX-809, a promising investigational corrector of DeltaF508-CFTR misprocessing, has limited clinical benefit and an incompletely understood mechanism, hampering drug development. Given the effect of second-site suppressor mutations, robust DeltaF508-CFTR correction most likely requires stabilization of NBD1 energetics and the interface between membrane-spanning domains (MSDs) and NBD1, which are both established primary conformational defects. Here we elucidate the molecular targets of available correctors: class I stabilizes the NBD1-MSD1 and NBD1-MSD2 interfaces, and class II targets NBD2. Only chemical chaperones, surrogates of class III correctors, stabilize human DeltaF508-NBD1. Although VX-809 can correct missense mutations primarily destabilizing the NBD1-MSD1/2 interface, functional plasma membrane expression of DeltaF508-CFTR also requires compounds that counteract the NBD1 and NBD2 stability defects in cystic fibrosis bronchial epithelial cells and intestinal organoids. Thus, the combination of structure-guided correctors represents an effective approach for cystic fibrosis therapy.|Aminopyridines/*pharmacology[MESH]|Animals[MESH]|Benzodioxoles/*pharmacology[MESH]|Binding Sites[MESH]|Bronchi/cytology[MESH]|Cell Membrane/metabolism[MESH]|Cricetinae[MESH]|Cystic Fibrosis Transmembrane Conductance Regulator/chemistry/*physiology[MESH]|Cystic Fibrosis/genetics/therapy[MESH]|Endoplasmic Reticulum/metabolism[MESH]|Epithelial Cells/metabolism[MESH]|Glycosylation[MESH]|Humans[MESH]|Mutation[MESH]|Nucleotides/chemistry[MESH]|Protein Folding[MESH]|Protein Structure, Tertiary[MESH]|Recombinant Proteins/chemistry[MESH] |
