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Antihypertensive 1,4-Dihydropyridines as Correctors of the Cystic Fibrosis Transmembrane Conductance Regulator Channel Gating Defect Caused by Cystic Fibrosis Mutations

Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, Genova, Italy (N.P., T.D., E.C., R.R., O.Z.-M., L.J.V.G.); Centro di Biotecnologie Avanzate, Genova, Italy (N.P., L.J.V.G.); and Dipartimento di Scienze Farmaceutiche, Università di Genova, Genova, Italy (E.N., M.M.)

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl^- channel gene. CF mutations like F508 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 thousand compounds were tested on Fischer rat thyroid cells coexpressing F508-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 antihypertensive 1,4-dihydropyridines (DHPs) nifedipine, nicardipine, nimodipine, isradipine, nitrendipine, felodipine, and niguldipine as compounds able to activate F508-CFTR. This effect was not derived from the inhibition of voltage-dependent Ca²⁺ channels, the pharmacological target of antihypertensive DHPs. Indeed, methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-2(trifluoromethylphenyl)pyridine-5-carboxylate (BayK-8644), a DHP that is effective as an activator of such channels, also stimulated CFTR activity. DHPs were also effective on the G551D-CFTR mutant by inducing a 16- to 45-fold increase of the CFTR 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.

Address correspondence to: Dr. Luis J. V. Galietta, Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, L.go Gerolamo Gaslini, 5, 16147 Genova, Italy. E-mail: galietta{at}unige.it

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