lumacaftor and cystic-fibrosis-transmembrane-conductance-regulator-(505-511)

Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Therapy, Combination; Humans; Peptide Fragments; Quinolones; Randomized Controlled Trials as Topic; Respiratory Function Tests

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.. 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.. 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.. The results from these studies can be interpreted as an equilibrium shift toward the open-channel conformation of F508del-CFTR channels.

Topics: Adenosine Triphosphate; Aminophenols; Aminopyridines; Benzodioxoles; Carrier Proteins; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; In Vitro Techniques; Intracellular Signaling Peptides and Proteins; Patch-Clamp Techniques; Peptide Fragments; Quinolones