title: Mechanism-based corrector combination restores ΔF508-CFTR folding and function.
abstract: The most common cystic fibrosis mutation, ΔF508 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 ΔF508-CFTR misprocessing, has limited clinical benefit and an incompletely understood mechanism, hampering drug development. Given the effect of second-site suppressor mutations, robust ΔF508-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 ΔF508-NBD1. Although VX-809 can correct missense mutations primarily destabilizing the NBD1-MSD1/2 interface, functional plasma membrane expression of ΔF508-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.
authors.affiliation: Department of Physiology, McGill University, Montréal, Quebec, Canada.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Okiyoneda
authors.forename: Guido
authors.initials: G
authors.lastname: Veit
authors.forename: Johanna F
authors.initials: JF
authors.lastname: Dekkers
authors.forename: Miklos
authors.initials: M
authors.lastname: Bagdany
authors.forename: Naoto
authors.initials: N
authors.lastname: Soya
authors.forename: Haijin
authors.initials: H
authors.lastname: Xu
authors.forename: Ariel
authors.initials: A
authors.lastname: Roldan
authors.forename: Alan S
authors.initials: AS
authors.lastname: Verkman
authors.forename: Mark
authors.initials: M
authors.lastname: Kurth
authors.forename: Agnes
authors.initials: A
authors.lastname: Simon
authors.forename: Tamas
authors.initials: T
authors.lastname: Hegedus
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Beekman
authors.forename: Gergely L
authors.initials: GL
authors.lastname: Lukacs
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology*; D001665:Binding Sites; D001980:Bronchi / Q000166:cytology; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003550:Cystic Fibrosis / Q000235:genetics / Q000628:therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D009154:Mutation; D009711:Nucleotides / Q000737:chemistry; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D000631:Aminopyridines; D052117:Benzodioxoles; D009711:Nucleotides; D011994:Recombinant Proteins; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C569105:lumacaftor