title: Identification of a novel water-soluble activator of wild-type and F508del CFTR: GPact-11a.
abstract: One of the major therapeutic strategy in cystic fibrosis aims at developing modulators of cystic fibrosis transmembrane conductance regulator (CFTR) channels. We recently discovered methylglyoxal alpha-aminoazaheterocycle adducts, as a new family of CFTR inhibitors. In a structure-activity relationship study, we have now identified GPact-11a, a compound able not to inhibit but to activate CFTR. Here, we present the effect of GPact-11a on CFTR activity using in vitro (iodide efflux, fluorescence imaging and patch-clamp recordings), ex vivo (short-circuit current measurements) and in vivo (salivary secretion) experiments. We report that GPact-11a: 1) is an activator of CFTR in several airway epithelial cell lines; 2) activates rescued F508del-CFTR in nasal, tracheal, bronchial, pancreatic cell lines and in human CF ciliated epithelial cells, freshly dissociated from lung samples; 3) stimulates ex vivo the colonic chloride secretion and increases in vivo the salivary secretion in cftr(+/+) but not cftr(-/-) mice; and 4) is selective for CFTR because its effect is inhibited by CFTR(inh)-172, GlyH-101, glibenclamide and GPinh-5a. To conclude, this work identifies a selective activator of wild-type and rescued F508del-CFTR. This nontoxic and water-soluble agent represents a good candidate, alone or in combination with a F508del-CFTR corrector, for the development of a CFTR modulator in cystic fibrosis.
authors.affiliation: Institut de Physiologie et Biologie Cellulaires, Université de Poitiers, CNRS UMR 6187, 40 Avenue du Recteur Pineau, 86022 Poitiers, France.
authors.forename: J
authors.initials: J
authors.lastname: Bertrand
authors.forename: B
authors.initials: B
authors.lastname: Boucherle
authors.forename: A
authors.initials: A
authors.lastname: Billet
authors.forename: P
authors.initials: P
authors.lastname: Melin-Heschel
authors.forename: L
authors.initials: L
authors.lastname: Dannhoffer
authors.forename: C
authors.initials: C
authors.lastname: Vandebrouck
authors.forename: C
authors.initials: C
authors.lastname: Jayle
authors.forename: C
authors.initials: C
authors.lastname: Routaboul
authors.forename: M-C
authors.initials: MC
authors.lastname: Molina
authors.forename: J-L
authors.initials: JL
authors.lastname: Décout
authors.forename: F
authors.initials: F
authors.lastname: Becq
authors.forename: C
authors.initials: C
authors.lastname: Norez
mesh_terms: D000225:Adenine / Q000737:chemistry*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D006801:Humans; D007454:Iodides / Q000737:chemistry; D008168:Lung / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence / Q000379:methods; D018408:Patch-Clamp Techniques; D011687:Purines / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D012463:Saliva / Q000378:metabolism; D012995:Solubility; D014867:Water / Q000737:chemistry
chemical_list: C505032:CFTR protein, human; C553660:Gpact-11a compound; D007454:Iodides; D011687:Purines; D011743:Pyrimidines; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D014867:Water; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000225:Adenine