Tan Xiao, Soualmia Feryel, Furio Laetitia, Renard Jean-François, Kempen Isabelle, Qin Lixian, Pagano Maurice, Pirotte Bernard, El Amri Chahrazade, Hovnanian Alain, Reboud-Ravaux Michèle
Sorbonne Universités, UPMC University Paris 06, UMR 8256, B2A, Biological Adaptation and Ageing, Integrated Cellular Ageing and Inflammation, Molecular & Functional Enzymology, Institut de Biologie Paris Seine , 7 Quai St Bernard, F-75005 Paris, France.
J Med Chem. 2015 Jan 22;58(2):598-612. doi: 10.1021/jm500988d. Epub 2014 Dec 22.
The inhibition of kallikreins 5 and 7, and possibly kallikrein 14 and matriptase, (that initiates the kallikrein proteolytic cascade) constitutes an innovative way to treat some skin diseases such as Netherton syndrome. We present here the inhibitory properties of coumarin-3-carboxylate derivatives against these enzymes. Our small collection of these versatile organic compounds was enriched by newly synthesized derivatives in order to obtain molecules selective against one, two, three enzymes or acting on the four ones. We evidenced a series of compounds with IC50 values in the nanomolar range. A suicide mechanism was observed against kallikrein 7 whereas the inactivation was either definitive (suicide type) or transient for kallikreins 5 and 14, and matriptase. Most of these potent inhibitors were devoid of cytotoxicity toward healthy human keratinocytes. In situ zymography investigations on skin sections from human kallikrein 5 transgenic mouse revealed significant reduction of the global proteolytic activity by several compounds.
抑制激肽释放酶5和7，可能还有激肽释放酶14和Matriptase（其启动激肽释放酶蛋白水解级联反应）构成了治疗某些皮肤病（如Netherton综合征）的创新方法。我们在此展示香豆素-3-羧酸酯衍生物对这些酶的抑制特性。我们收集的这些多功能有机化合物的小样本通过新合成的衍生物得以丰富，以获得对一种、两种、三种酶具有选择性或作用于这四种酶的分子。我们证明了一系列IC50值在纳摩尔范围内的化合物。观察到针对激肽释放酶7的自杀机制，而对于激肽释放酶5和14以及Matriptase，失活要么是确定的（自杀类型），要么是短暂的。这些强效抑制剂中的大多数对健康的人角质形成细胞无细胞毒性。对人激肽释放酶5转基因小鼠皮肤切片进行的原位酶谱分析表明，几种化合物可显著降低整体蛋白水解活性。
