Background. Cystic fibrosis (CF) is a frequent and lethal genetic disease caused by mutations associated with the CF transmembrane regulator (CFTR), a chloride channel located in the apical membrane of epithelial cells lining the ducts. In nearly 70% of the CF patients, the mutation involved is a deletion of phenylalanine at position 508 of the protein (DF-CFTR). The mutant protein cannot fold properly leading to its intracellular retention and degradation. Pharmacological screening approaches have identified small molecule “correctors” (which promote a modest level of DF-CFTR arrival at the plasma membrane), some of which are in clinical trials. Unfortunately, their mode of action is not known.
Hypothesis and objectives. We proposed to develop a rational basis for the pharmacological correction of DF-CFTR defects, by characterizing the mechanism of action of correctors, to identify molecular components and pathways involved in the correction and then targeting them by efficient ways.