Muenster University Hospital, Institute of Physiological Chemistry and Pathobiochemistry, Waldeyerstr. 15, D-48129 Muenster, Germany.
J Cell Biochem. 2012 Jan;113(1):156-64. doi: 10.1002/jcb.23339.
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.
我们最近发现，透明质酸由 MRP5 从成纤维细胞中输出，由囊性纤维化跨膜电导调节因子（CFTR）从上皮细胞中输出，CFTR 是已知的氯离子通道。在此基础上，我们开发了透明质酸二糖的膜通透性类似物作为一类新的化合物来修饰它们的外排。我们发现了能够激活人乳腺癌细胞透明质酸外排的物质。最活跃的化合物 2-(2-乙酰胺基-3,5-二羟基苯氧基）-5-氨基苯甲酸（Hylout4）被测试其对上皮细胞活性的影响。它通过正常和缺陷的 ΔF508-CFTR 激活离子外排。它还增加了 ΔF508-CFTR 蛋白的质膜浓度，并降低了上皮细胞的跨上皮电阻。在健康人的人体试验中，它导致鼻上皮 CFTR 的开放。因此，化合物 Hylout4 是一种纠正剂，可从细胞内降解中恢复 ΔF508-CFTR 并激活其外排功能。
