Nanomolar affinity small molecule correctors of defective ΔF508-CFTR chloride channel gating

Hong Yang, Anang A. Shelat, R. Kiplin Guy, Vadiraj S. Gopinath, Tonghui Ma, Kai Du, Gergely L. Lukacs, Alessandro Taddei, Chiara Folli, Nicoletta Pedemonte, Luis J.V. Galietta, A. S. Verkman

Research output: Contribution to journalArticlepeer-review

201 Scopus citations


Deletion of Phe-508 (ΔF508) is the most common mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) causing cystic fibrosis. ΔF508-CFTR has defects in both channel gating and endoplasmic reticulum-to-plasma membrane processing. We identified six novel classes of high affinity potentiators of defective ΔF508-CFTR Cl- channel gating by screening 100,000 diverse small molecules. Compounds were added 15 min prior to assay of iodide uptake in epithelial cells co-expressing ΔF508-CFTR and a high sensitivity halide indicator (YFP-H148Q/I152L) in which ΔF508-CFTR was targeted to the plasma membrane by culture at 27 °C for 24 h. Thirty-two compounds with submicromolar activating potency were identified; most had tetrahydrobenzothiophene, benzofuran, pyramidinetrione, dihydropyridine, and anthraquinone core structures (360-480 daltons). Further screening of > 1000 structural analogs revealed tetrahydrobenzothiophenes that activated ΔF508-CFTR Cl- conductance reversibly with Kd < 100 nM. Single-cell voltage clamp analysis showed characteristic CFTR currents after ΔF508-CFTR activation. Activation required low concentrations of a cAMP agonist, thus mimicking the normal physiological response. A Bayesian computational model was developed using tetrahydrobenzothiophene structure-activity data, yielding insight into the physical character and structural features of active and inactive potentiators and successfully predicting the activity of structural analogs. Efficient potentiation of defective ΔF508-CFTR gating was also demonstrated in human bronchial epithelial cells from a ΔF508 cystic fibrosis subject after 27 °C temperature rescue. In conjunction with correctors of defective ΔF508-CFTR processing, small molecule potentiators of defective ΔF508-CFTR gating may be useful for therapy of cystic fibrosis caused by the ΔF508 mutation.

Original languageEnglish
Pages (from-to)35079-35085
Number of pages7
JournalJournal of Biological Chemistry
Issue number37
StatePublished - Sep 12 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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