title: Combined effects of VX-770 and VX-809 on several functional abnormalities of F508del-CFTR channels.
abstract: 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.
authors.affiliation: Department of Physics and Astronomy, University of Missouri, Columbia, MO 65211, USA; Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Kopeikin
authors.affiliation: Department of Physics and Astronomy, University of Missouri, Columbia, MO 65211, USA; Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Yuksek
authors.affiliation: Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Yang
authors.affiliation: Department of Physics and Astronomy, University of Missouri, Columbia, MO 65211, USA; Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA. Electronic address: BompadreS@missouri.edu.
authors.forename: S G
authors.initials: SG
authors.lastname: Bompadre
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000627:Aminophenols / Q000494:pharmacology* / Q000627:therapeutic use; D000631:Aminopyridines / Q000494:pharmacology* / Q000627:therapeutic use; D052117:Benzodioxoles / Q000494:pharmacology* / Q000627:therapeutic use; D002352:Carrier Proteins / Q000378:metabolism; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments; D015363:Quinolones / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000627:Aminophenols; D000631:Aminopyridines; D052117:Benzodioxoles; C505032:CFTR protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C089765:NUBP1 protein, human; D010446:Peptide Fragments; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C074197:cystic fibrosis transmembrane conductance regulator (505-511); C545203:ivacaftor; D000255:Adenosine Triphosphate; C569105:lumacaftor
keywords: Cystic fibrosis; Electrophysiology; Pharmacology; VX-770; VX-809