Small-molecule correctors of defective DeltaF508-CFTR cellular processing identified by high-throughput screening

J Clin Invest. 2005 Sep;115(9):2564-71. doi: 10.1172/JCI24898. Epub 2005 Aug 25.


The most common cause of cystic fibrosis (CF) is deletion of phenylalanine 508 (DeltaF508) in the CF transmembrane conductance regulator (CFTR) chloride channel. The DeltaF508 mutation produces defects in folding, stability, and channel gating. To identify small-molecule correctors of defective cellular processing, we assayed iodide flux in DeltaF508-CFTR-transfected epithelial cells using a fluorescent halide indicator. Screening of 150,000 chemically diverse compounds and more than 1,500 analogs of active compounds yielded several classes of DeltaF508-CFTR correctors (aminoarylthiazoles, quinazolinylaminopyrimidinones, and bisaminomethylbithiazoles) with micromolar potency that produced greater apical membrane chloride current than did low-temperature rescue. Correction was seen within 3-6 hours and persisted for more than 12 hours after washout. Functional correction was correlated with plasma membrane expression of complex-glycosylated DeltaF508-CFTR protein. Biochemical studies suggested a mechanism of action involving improved DeltaF508-CFTR folding at the ER and stability at the cell surface. The bisaminomethylbithiazoles corrected DeltaF508-CFTR in DeltaF508/DeltaF508 human bronchial epithelia but did not correct a different temperature-sensitive CFTR mutant (P574H-CFTR) or a dopamine receptor mutant. Small-molecule correctors may be useful in the treatment of CF caused by the DeltaF508 mutation.

Publication types

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

MeSH terms

  • Animals
  • Cells, Cultured
  • Colforsin / metabolism
  • Cystic Fibrosis / drug therapy
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Drug Design
  • Enzyme Inhibitors / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / physiology*
  • Genistein / metabolism
  • Humans
  • Iodides / chemistry
  • Iodides / metabolism
  • Luminescent Proteins / chemistry
  • Luminescent Proteins / metabolism
  • Molecular Structure
  • Mutation
  • Pyrimidinones / chemistry
  • Pyrimidinones / metabolism*
  • Pyrimidinones / therapeutic use
  • Respiratory Mucosa / cytology
  • Thiazoles / chemistry
  • Thiazoles / metabolism*
  • Thiazoles / therapeutic use


  • Enzyme Inhibitors
  • Iodides
  • Luminescent Proteins
  • Pyrimidinones
  • Thiazoles
  • cystic fibrosis transmembrane conductance regulator delta F508
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Colforsin
  • Genistein