Evaluation of a systems biology approach to identify pharmacological correctors of the mutant CFTR chloride channel

BackgroundMistrafficking of CFTR protein caused by F508del, the most frequent mutation in cystic fibrosis (CF), can be corrected by cell incubation at low temperature, an effect that may be mediated by altered expression of proteostasis genes.MethodsTo identify small molecules mimicking low temperature, we compared gene expression profiles of cells kept at 27 °C with those previously generated from more than 1300 compounds. The resulting candidates were tested with a functional assay on a bronchial epithelial cell line.ResultsWe found that anti-inflammatory glucocorticoids, such as mometasone, budesonide, and fluticasone, increased mutant CFTR function. However, this activity was not confirmed in primary bronchial epithelial cells. Actually, glucocorticoids enhanced Na+ absorption, an effect that could further impair mucociliary clearance in CF airways.ConclusionsOur results suggest that rescue of F508del-CFTR by low temperature cannot be easily mimicked by small molecules and that compounds with closer transcriptional and functional effects need to be found.

Graphical abstractDownload high-res image (283KB)Download full-size image