Searching for Combinations of Small-Molecule Correctors to Restore F508del–Cystic Fibrosis Transmembrane Conductance Regulator Function and Processing

The mutated protein F508del–cystic fibrosis transmembrane conductance regulator (CFTR) failed to traffic properly as a re-sult of its retention in the endoplasmic reticulum and functions as a chloride (Cl2) channel with abnormal gating and endocytosis. Small chemicals (called correctors) individually restore F508del-CFTR trafficking and Cl2 transport function, but recent findings indicate that synergistic pharmacology should be considered to address CFTR defects more clearly. We studied the function and maturation of F508del-CFTR expressed in HeLa cells using a combination of five correctors [miglustat, IsoLAB (1,4-dideoxy-2-hydroxymethyl-1,4-imino-L-threitol), Corr4a (N-[2-(5-chloro-2-methoxy-phenylamino)-49-methyl-[4,59]bithiazolyl-29-yl]-benzamide)