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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.
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Contributor : Christelle Morillon Connect in order to contact the contributor
Submitted on : Tuesday, January 25, 2011 - 10:08:57 AM
Last modification on : Wednesday, October 20, 2021 - 3:22:04 AM

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J. Bertrand, B. Boucherle, A. Billet, P. Melin-Heschel, L. Dannhoffer, et al.. Identification of a novel water-soluble activator of wild-type and F508del CFTR: GPact-11a.. European Respiratory Journal, European Respiratory Society, 2010, 36 (2), pp.311-22. ⟨10.1183/09031936.00122509⟩. ⟨hal-00559199⟩



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