Background: The most common cystic fibrosis-associated mutation, the deletion of phenylalanine 508 (F508del), results in channels with poor membrane expression and impaired function. VX-770, a clinically approved drug for treatment of CF patients carrying the G551D mutation, and VX-809, a corrector shown in vitro to increase membrane expression of mutant channels, are currently undergoing clinical trials, but functional data at the molecular level is still lacking.
Methods: The effect of VX-770 and VX-809 on the multiple functional defects of F508del-CFTR was assessed via excised inside-out patch-clamp experiments.
Results: VX-770 completely restores the low opening-rate of F508del-CFTR, with smaller open-time increase, in temperature-corrected and VX-809-treated channels. The shorter locked-open time of hydrolysis-deficient F508del-CFTR is also prolonged by VX-770. VX-809 does not improve channel function by itself as previously reported.
Conclusions: The results from these studies can be interpreted as an equilibrium shift toward the open-channel conformation of F508del-CFTR channels.
Keywords: Cystic fibrosis; Electrophysiology; Pharmacology; VX-770; VX-809.
Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.