title: Recovery of ΔF508-CFTR function by analogs of hyaluronan disaccharide.
abstract: We recently discovered that hyaluronan was exported from fibroblasts by MRP5 and from epithelial cells by cystic fibrosis (CF) transmembrane conductance regulator (CFTR) that was known as a chloride channel. On this basis we developed membrane permeable analogs of hyaluronan disaccharide as new class of compounds to modify their efflux. We found substances that activated hyaluronan export from human breast cancer cells. The most active compound 2-(2-acetamido-3,5-dihydroxyphenoxy)-5-aminobenzoic acid (Hylout4) was tested for its influence on the activity of epithelial cells. It activated the ion efflux by normal and defective ΔF508-CFTR. It also enhanced the plasma membrane concentration of the ΔF508-CFTR protein and reduced the transepithelial resistance of epithelial cells. In human trials of healthy persons, it caused an opening of CFTR in the nasal epithelium. Thus compound Hylout4 is a corrector that recovered ΔF508-CFTR from intracellular degradation and activated its export function.
authors: Muenster University Hospital, Institute of Physiological Chemistry and Pathobiochemistry, Waldeyerstr. 15, D-48129 Muenster, Germany.
authors: Ewa
authors: E
authors: Nowakowska
authors: Tobias
authors: T
authors: Schulz
authors: Natalia
authors: N
authors: Molenda
authors: Hermann
authors: H
authors: Schillers
authors: Peter
authors: P
authors: Prehm
mesh_terms: D000083:Acetanilides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D062365:Aminobenzoates / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D001693:Biological Transport, Active; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid / Q000031:analogs & derivatives / Q000378:metabolism*; D007454:Iodides / Q000378:metabolism; D017136:Ion Transport; D009297:Nasal Mucosa / Q000378:metabolism; D062368:meta-Aminobenzoates
chemical_list: C572720:2-(2-acetamido-3,5-dihydroxyphenoxy)-5-aminobenzoic acid; D000083:Acetanilides; D062365:Aminobenzoates; D007454:Iodides; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D062368:meta-Aminobenzoates; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D006820:Hyaluronic Acid