Mechanism-based corrector combination restores ΔF508-CFTR folding and function

Nat Chem Biol. 2013 Jul;9(7):444-54. doi: 10.1038/nchembio.1253. Epub 2013 May 12.


The most common cystic fibrosis mutation, ΔF508 in nucleotide binding domain 1 (NBD1), impairs cystic fibrosis transmembrane conductance regulator (CFTR)-coupled domain folding, plasma membrane expression, function and stability. VX-809, a promising investigational corrector of ΔF508-CFTR misprocessing, has limited clinical benefit and an incompletely understood mechanism, hampering drug development. Given the effect of second-site suppressor mutations, robust ΔF508-CFTR correction most likely requires stabilization of NBD1 energetics and the interface between membrane-spanning domains (MSDs) and NBD1, which are both established primary conformational defects. Here we elucidate the molecular targets of available correctors: class I stabilizes the NBD1-MSD1 and NBD1-MSD2 interfaces, and class II targets NBD2. Only chemical chaperones, surrogates of class III correctors, stabilize human ΔF508-NBD1. Although VX-809 can correct missense mutations primarily destabilizing the NBD1-MSD1/2 interface, functional plasma membrane expression of ΔF508-CFTR also requires compounds that counteract the NBD1 and NBD2 stability defects in cystic fibrosis bronchial epithelial cells and intestinal organoids. Thus, the combination of structure-guided correctors represents an effective approach for cystic fibrosis therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / pharmacology*
  • Animals
  • Benzodioxoles / pharmacology*
  • Binding Sites
  • Bronchi / cytology
  • Cell Membrane / metabolism
  • Cricetinae
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / therapy
  • Cystic Fibrosis Transmembrane Conductance Regulator / chemistry
  • Cystic Fibrosis Transmembrane Conductance Regulator / physiology*
  • Endoplasmic Reticulum / metabolism
  • Epithelial Cells / metabolism
  • Glycosylation
  • Humans
  • Mutation
  • Nucleotides / chemistry
  • Protein Folding
  • Protein Structure, Tertiary
  • Recombinant Proteins / chemistry


  • Aminopyridines
  • Benzodioxoles
  • Nucleotides
  • Recombinant Proteins
  • cystic fibrosis transmembrane conductance regulator delta F508
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • lumacaftor