Synergy-Based Small-Molecule Screen Using a Human Lung Epithelial Cell Line Yields ΔF508-CFTR Correctors That Augment VX-809 Maximal Efficacy

• Published in: Molecular pharmacology Vol. 86; no. 1; pp. 42 - 51
• Main Authors: Phuan, Puay-Wah, Veit, Guido, Tan, Joseph, Roldan, Ariel, Finkbeiner, Walter E., L. Lukacs, Gergely, Verkman, A.S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2014; The American Society for Pharmacology and Experimental Therapeutics
• Subjects: Aminopyridines - pharmacology; Animals; Benzodioxoles - pharmacology; Biological Transport - drug effects; Biological Transport - genetics; Bronchi - drug effects; Bronchi - metabolism; Cell Line; Chlorides - metabolism; Cystic Fibrosis - drug therapy; Cystic Fibrosis - metabolism; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Dogs; Drug Synergism; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Horseradish Peroxidase - metabolism; Humans; Lung - drug effects; Lung - metabolism; Madin Darby Canine Kidney Cells; Mutation - drug effects; Mutation - genetics; Permeability - drug effects; Protein Folding - drug effects; Protein Structure, Tertiary - drug effects; Protein Structure, Tertiary - genetics; Respiratory Mucosa - drug effects; Respiratory Mucosa - metabolism; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; PBS; YFP; CF; DMSO; HRP; VX-770; ER; C4; NBD; FBS; VX-809; CFBE; HA; CFTR; ELISA; MSD

The most prevalent cystic fibrosis transmembrane conductance regulator (CFTR) mutation causing cystic fibrosis, ΔF508, impairs folding of nucleotide binding domain (NBD) 1 and stability of the interface between NBD1 and the membrane-spanning domains. The interfacial stability defect can be partially...