The mutated protein F508del–cystic fibrosis transmembrane conductance regulator (CFTR) failed to traffic properly and function as a Cl− channel. Small-molecule correctors individually restore F508del-CFTR trafficking and Cl− transport function, but recent findings suggest that synergistic pharmacology may better address CFTR defects. This study investigated the function and maturation of F508del-CFTR expressed in HeLa cells with 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)-4′-methyl-[4,5′]bithiazolyl-2′-yl]-benzamide), VX-809 [3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid], and suberoylamilide hydroxamic acid (SAHA)]. The current density recorded in response to CFTR activators (forskolin + genistein) was significantly increased in presence of the following combinations: VX-809+IsoLAB; VX-809 + miglustat + SAHA; VX-809 + miglustat + IsoLAB; VX-809 + IsoLAB + SAHA; VX-809 + miglustat + IsoLAB + SAHA. These combinations restored the activity of F508del-CFTR but with differential effect on the appearance of mature c-band of F508del-CFTR proteins. These results open new perspectives for the development of a synergistic polypharmacology to rescue F508del-CFTR.
See article at J Pharmacol Exp Ther 2014, 350:624–634.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics