Influence of cell background on pharmacological rescue of mutant CFTR

Nicoletta Pedemonte, Valeria Tomati, Elvira Sondo, Luis J V Galietta

Research output: Contribution to journalArticlepeer-review


Cystic fibrosis (CF) is caused by mutations in the CFTR chloride channel. Deletion of phenylalanine 508 (F508del), the most frequent CF mutation, impairs the maturation and gating of the CFTR protein. Such defects may be corrected in vitro by pharmacological modulators named as correctors and potentiators, respectively. We have evaluated a panel of correctors and potentiators derived from various sources to assess potency, efficacy, and mechanism of action. For this purpose, we have used functional and biochemical assays on two different cell expression systems, Fischer rat thyroid (FRT) and A549 cells. The order of potency and efficacy of potentiators was similar in the two cell types considered, with phenylglycine PG-01 and isoxazole UCCF-152 being the most potent and least potent, respectively. Most potentiators were also effective on two mutations, G551D and G1349D, that cause a purely gating defect. In contrast, corrector effect was strongly affected by cell background, with the extreme case of many compounds working in one cell type only. Our findings are in favor of a direct action of potentiators on CFTR, possibly at a common binding site. In contrast, most correctors seem to work indirectly with various mechanisms of action. Combinations of correctors acting at different levels may lead to additive F508del-CFTR rescue.

Original languageEnglish
JournalAmerican Journal of Physiology - Cell Physiology
Issue number4
Publication statusPublished - Apr 2010


  • Chloride channel
  • Cystic fibrosis
  • Drug discovery
  • High-throughput screening

ASJC Scopus subject areas

  • Cell Biology
  • Physiology


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