Combined effects of VX-770 and VX-809 on several functional abnormalities of F508del-CFTR channels

J Cyst Fibros. 2014 Sep;13(5):508-14. doi: 10.1016/j.jcf.2014.04.003. Epub 2014 May 3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Aminophenols / pharmacology*
  • Aminophenols / therapeutic use
  • Aminopyridines / pharmacology*
  • Aminopyridines / therapeutic use
  • Benzodioxoles / pharmacology*
  • Benzodioxoles / therapeutic use
  • Carrier Proteins / metabolism
  • Cystic Fibrosis / drug therapy
  • Cystic Fibrosis / genetics*
  • Cystic Fibrosis / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator / physiology*
  • Humans
  • In Vitro Techniques
  • Intracellular Signaling Peptides and Proteins
  • Patch-Clamp Techniques
  • Peptide Fragments
  • Quinolones / pharmacology*
  • Quinolones / therapeutic use


  • Aminophenols
  • Aminopyridines
  • Benzodioxoles
  • CFTR protein, human
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • NUBP1 protein, human
  • Peptide Fragments
  • Quinolones
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • cystic fibrosis transmembrane conductance regulator (505-511)
  • ivacaftor
  • Adenosine Triphosphate
  • lumacaftor