Benzoflavone activators of the cystic fibrosis transmembrane conductance regulator: towards a pharmacophore model for the nucleotide-binding domain

Regulatory domain phosphorylation to distinguish the mechanistic basis underlying acute CFTR modulators

“…Forskolin (20 M) treatments were for 5 min and H89 (10 M) pretreatment for 20 min. Potentiator treatments were at the previously published EC 50 (VRT-532, 5 M; UC CF-152, 50 M; PG-01, 300 nM; SF-03, 30 nM; UCCF-853, 3 M; ⌬F508 act-02, 70 nM; genistein, 30 M; UCCF-029, 2 M; UCCF-180, 10 M) (7,26,32,37,41,51), except where otherwise specified. After drug treatment, cells were lysed in buffer (1% NP-40, 50 mM Tris·HCl, pH 7.5, 200 mM NaCl, 5 mM MgCl 2, 15% glycerol) with protease (Complete mini protease cocktail, Roche Diagnostics) and phosphatase inhibitors [Na 3VO4 (0.2 mM), NaF (10 mM), MoO4 (1 mM), and ␤-glycerophosphate (50 mM)].…”

Development and Investigation of Dry Powder Inhalers for Cystic Fibrosis

“…1) extracted from grapefruits has shown anti-inflammatory, antioxidant and anticarcinogenic effects [18]. In addition, recent studies have reported that flavonoids may act as CFTR direct activators, stimulating transepithelial chloride transport [19][20][21]. Although flavonoids are inhibitors of tyrosine kinases and phosphatases, their effects on CFTR are probably independent of these activities, resulting from direct binding to an NBD of phosphorylated CFTR [22].…”

“…With the aim to discover more effective activators of G551D-CFTR [19], some investigators have begun to examine the relationship between the chemical structure of flavonoids and their effects on CFTR Cl¦ channels. This study served to identify the pharmacophore portion of the skeletons molecular basis for interaction with the NBD.…”

Activation of the Cystic Fibrosis Transmembrane Conductance Regulator by the Flavonoid Quercetin

“…If cAMP-dependent activation is defective in human airway cells expressing surface-localized DF508 CFTR, the identification of a molecule capable of activating the mutant channel that is also suitable for use in NPD protocols may improve the sensitivity of the assay to detect DF508 CFTR at the cell surface. Because flavonoids are among the best-described activators of CFTR activity (15)(16)(17), we sought to determine the most suitable agent that could be applied to the measurement of NPD. Some results of these studies were previously reported in abstracts (18,19).…”