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Research ArticleCellular and Molecular

Searching for Combinations of Small-Molecule Correctors to Restore F508del–Cystic Fibrosis Transmembrane Conductance Regulator Function and Processing

Clément Boinot, Mathilde Jollivet Souchet, Romain Ferru-Clément and Frédéric Becq
Journal of Pharmacology and Experimental Therapeutics September 2014, 350 (3) 624-634; DOI: https://doi.org/10.1124/jpet.114.214890
Clément Boinot
Laboratoire Signalisation et Transports Ioniques Membranaires, Université de Poitiers, Centre National de la Recherche Scientifique (CNRS), Poitiers, France
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Mathilde Jollivet Souchet
Laboratoire Signalisation et Transports Ioniques Membranaires, Université de Poitiers, Centre National de la Recherche Scientifique (CNRS), Poitiers, France
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Romain Ferru-Clément
Laboratoire Signalisation et Transports Ioniques Membranaires, Université de Poitiers, Centre National de la Recherche Scientifique (CNRS), Poitiers, France
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Frédéric Becq
Laboratoire Signalisation et Transports Ioniques Membranaires, Université de Poitiers, Centre National de la Recherche Scientifique (CNRS), Poitiers, France
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Abstract

The mutated protein F508del–cystic fibrosis transmembrane conductance regulator (CFTR) failed to traffic properly as a result of its retention in the endoplasmic reticulum and functions as a chloride (Cl−) channel with abnormal gating and endocytosis. Small chemicals (called correctors) individually restore F508del-CFTR trafficking and Cl− transport function, but recent findings indicate that synergistic pharmacology should be considered to address CFTR defects more clearly. We studied the function and maturation of F508del-CFTR expressed in HeLa cells using a combination of five correctors [miglustat, IsoLAB (1,4-dideoxy-2-hydroxymethyl-1,4-imino-l-threitol), Corr4a (N-[2-(5-chloro-2-methoxy-phenylamino)-4′-methyl-[4,5′]bithiazolyl-2′-yl]-benzamide), VX-809 [3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid], and suberoylamilide hydroxamic acid (SAHA)]. Using the whole-cell patch-clamp technique, the current density recorded in response to CFTR activators (forskolin + genistein) was significantly increased in the presence of the following combinations: VX-809 + IsoLAB; VX-809 + miglustat + SAHA; VX-809 + miglustat + IsoLAB; VX-809 + IsoLAB + SAHA; VX-809 + miglustat + IsoLAB + SAHA. These combinations restored the activity of F508del-CFTR but with a differential effect on the appearance of mature c-band of F508del-CFTR proteins. Focusing on the VX-809 + IsoLAB cocktail, we recorded a level of correction higher at 37°C versus room temperature, but without amelioration of the thermal instability of CFTR. The level of functional rescue with VX-809 + IsoLAB after 4 hours of incubation was maximal and similar to that obtained in optimal conditions of use for each compound (i.e., 24 hours for VX-809 + 4 hours for IsoLAB). Finally, we compared the stimulation of F508del-CFTR by forskolin or forskolin + VX-770 [N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide] with cells corrected by VX-809 + IsoLAB. Our results open new perspectives for the development of a synergistic polypharmacology to rescue F508del-CFTR and show the importance of temperature on the effect of correctors and on the level of correction, suggesting that optimized combination of correctors could lead to a better rescue of F508del-CFTR function.

Footnotes

    • Received March 24, 2014.
    • Accepted June 23, 2014.
  • This work was supported by grants from Vaincre La Mucoviscidose (Paris, France) and Université de Poitiers. C.B. was supported by a Ph.D. fellowship from Vaincre La Mucoviscidose. M.J.S. was supported by a donation from the charities “Mucovie” (Perpignan, France) and “Amandine contre la mucoviscidose” (Dijon, France).

  • dx.doi.org/10.1124/jpet114.214890.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 350 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 350, Issue 3
1 Sep 2014
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Research ArticleCellular and Molecular

Combination of F508del-CFTR Correctors

Clément Boinot, Mathilde Jollivet Souchet, Romain Ferru-Clément and Frédéric Becq
Journal of Pharmacology and Experimental Therapeutics September 1, 2014, 350 (3) 624-634; DOI: https://doi.org/10.1124/jpet.114.214890

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Research ArticleCellular and Molecular

Combination of F508del-CFTR Correctors

Clément Boinot, Mathilde Jollivet Souchet, Romain Ferru-Clément and Frédéric Becq
Journal of Pharmacology and Experimental Therapeutics September 1, 2014, 350 (3) 624-634; DOI: https://doi.org/10.1124/jpet.114.214890
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