Anti-hypertensive dihydropyridines as correctors of the CFTR channel gating defect caused by Cystic Fibrosis mutations

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel gene. CF mutations like DeltaF508 cause both a mistrafficking of the protein and a gating defect. Other mutations, like G551D, cause only a gating defect. Our aim was to find chemical compounds able to stimulate the activity of CFTR mutant proteins by screening a library containing approved drugs. Two thousands compounds were tested on Fisher rat thyroid cells co-expressing DeltaF508-CFTR and a halide-sensitive yellow fluorescent protein (YFP) after correction of the trafficking defect by low-temperature incubation. The YFP-based screening allowed the identification of the anti-hypertensive 1,4-dihydropyridines (DHPs) nifedipine, nicardipine, nimodipine, isradipine, nitrendipine, felodipine and niguldipine as compounds able to activate DeltaF508-CFTR. This effect was not derived from the inhibition of voltage-dependent Ca2+ channels, the pharmacological target of anti-hypertensive DHPs. Indeed, methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-2(trifluoromethylphenyl)pyridine-5-carboxilate (BayK-8644), a DHP that is effective as an activator of such channels, also stimulate CFTR activity. DHPs were also effective on the G551D-CFTR mutant by inducing a 16- to 45-fold increase of the CFTRT Cl- currents. DHP activity was confirmed in airway epithelial cells from patients with CF. DHPs may represent a novel class of therapeutic agents able to correct the defect caused by a set of CF mutations.