RT Journal Article SR Electronic T1 Correction of ΔF508-CFTR trafficking defect by the bioavailable compound glafenine JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.109.062679 DO 10.1124/mol.109.062679 A1 Renaud Robert A1 Graeme C Carlile A1 Jie Liao A1 Haouaria Balghi A1 Pierre Lesimple A1 Na Liu A1 Bart Kus A1 Daniela Rotin A1 Martina Wilke A1 Hugo R de Jonge A1 Bob J Scholte A1 David Y Thomas A1 John W Hanrahan YR 2010 UL http://molpharm.aspetjournals.org/content/early/2010/03/03/mol.109.062679.abstract AB Cystic Fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes a cAMP-activated anion channel expressed in epithelial cells. The most common mutation ΔF508 leads to protein misfolding, retention by the endoplasmic reticulum, and degradation. One promising therapeutic approach is to identify drugs that have been developed for other indications but which also correct the CFTR trafficking defect, thereby exploiting their known safety and bioavailability in humans and reducing the time required for clinical development. We have screened approved, marketed and off-patent drugs with known safety and bioavailability using a ΔF508-CFTR trafficking assay. Among the confirmed hits was glafenine, an anthranilic acid derivative with analgesic properties. Its ability to correct the misprocessing of CFTR was confirmed by in vitro and in vivo studies using a concentration that is achieved clinically in plasma (10 μM). Glafenine increased the surface expression of ΔF508-CFTR in BHK cells to ~ 40% of that observed for wt-CFTR, comparable to the known CFTR corrector VRT-325. Partial correction was confirmed by the appearance of mature CFTR in Western blots and by two assays of halide permeability in unpolarized BHK and HEK cells. Incubating polarized CFBE41o- monolayers and intestines isolated from ΔF508-CFTR mice (treated ex-vivo) with glafenine increased the short-circuit current (Isc) response to forskolin + genistein, and this effect was abolished by 10 μM CFTRinh172. In vivo treatment with glafenine also partially restored total salivary secretion. We conclude that the discovery of glafenine as a CFTR corrector validates the approach of investigating existing drugs for the treatment of CF, although localized delivery or further medicinal chemistry may be needed to reduce side-effects.The American Society for Pharmacology and Experimental Therapeutics