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 a-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.

Impairment in inflammasome signaling by the chronic Pseudomonas aeruginosa isolates from cystic fibrosis patients results in an increase in inflammatory response

“…We sought to investigate if inhibition of CFTR function impacted inflammatory cell death and cytokine expression by macrophages and epithelial cells. We treated THP-1 macrophages overnight with the CFTR-selective inhibitor (CFTR(inh)-172) using a previously reported concentration of 10 µM [20][21][22][23] and infected them with PA14 or PAO1. No clear impact of the CFTR inhibitor was observed in cell death or cytokine expression during PA14 (Fig.…”

Identification of Synergistic Combinations of F508del Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators

“…Surprisingly, histone deacetylase (HDAC) inhibitors, from multiple structural classes, including hydroxamic acids (suberoylanilide hydroxamic acid [SAHA]), benzamides (MS-275), cyclic peptides (apicidin), and short chain fatty acids (sodium butyrate and valproate), performed as well as the reference tool compounds 48 (Table 1). Several glucocorticoids (GCs) and statins were also active in the corrector protocol, but showed smaller effects that reached a plateau between 1.2 and 1.4-fold of NQR over control ( Table 1).…”

A functional tandem between transient receptor potential canonical channels 6 and calcium-dependent chloride channels in human epithelial cells

“…Details are as described in (Bertrand, et al, 2010). All participants were informed, and provided their written consent before surgery.…”

“…Abbreviations: BK ca channels, large-conductance Ca 2+-activated K + channels; CaCC, Ca 2+ dependent Cl -channel; CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; CFTRinh-172, 3 Moli1901 (2622U90 or duramycin) is a peptide drug that increases chloride transport when applied to airway epithelium (Zeitlin, et al, 2004). This peptide interacts with phospholipids present in membranes, where it elevates [Ca 2+ ]i and in turn activates an alternative chloride conductance pathway (Cloutier, et al, 1993).…”