A common mechanism for CFTR potentiators

The Journal of General Physiology
Han-I YehTzyh-Chang Hwang

Abstract

Cystic fibrosis (CF) is a channelopathy caused by loss-of-function mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a phosphorylation-activated and adenosine triphosphate (ATP)-gated chloride channel. In the past few years, high-throughput drug screening has successfully realized the first US Food and Drug Administration-approved therapy for CF, called ivacaftor (or VX-770). A more recent CFTR potentiator, GLPG1837 (N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-3-carboxamide), has been shown to exhibit a higher efficacy than ivacaftor for the G551D mutation, yet the underlying mechanism of GLPG1837 remains unclear. Here we find that despite their differences in potency and efficacy, GLPG1837 and VX-770 potentiate CFTR gating in a remarkably similar manner. Specifically, they share similar effects on single-channel kinetics of wild-type CFTR. Their actions are independent of nucleotide-binding domain (NBD) dimerization and ATP hydrolysis, critical steps controlling CFTR's gate opening and closing, respectively. By applying the two reagents together, we provide evidence that GLPG1837 and VX-770 likely compete for the same site, whereas GLPG183...Continue Reading

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Citations

Dec 6, 2018·Physiological Reviews·László CsanádyDavid C Gadsby
Feb 10, 2019·Biological Chemistry·Xin MengRobert C Ford
Jun 18, 2019·ELife·László Csanády, Beáta Töröcsik
Oct 5, 2019·The Journal of Physiology·Jiunn-Tyng Yeh, Tzyh-Chang Hwang
Jun 6, 2019·The Journal of General Physiology·Han-I YehTzyh-Chang Hwang
Mar 28, 2018·The Journal of General Physiology·Tzyh-Chang HwangSamantha Destefano
Mar 16, 2019·Frontiers in Pharmacology·Iwona PrankeIsabelle Sermet-Gaudelus
Nov 17, 2019·The Journal of Pharmacology and Experimental Therapeutics·Ashvani K SinghChris Tse
Nov 13, 2018·Frontiers in Pharmacology·Maarten GeesKatja Conrath
Mar 11, 2020·Frontiers in Pharmacology·Miquéias Lopes-Pacheco
Sep 17, 2020·Human Mutation·Stefano DonegàFranco Pagani
Feb 23, 2020·European Journal of Medicinal Chemistry·Lionel FrouxJean-Luc Décout
Jan 6, 2021·Journal of Medicinal Chemistry·Steven E Van der PlasMartin Andrews
Nov 25, 2019·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Bertrand KleizenDavid N Sheppard

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