咪唑衍生的2-[N-氨甲酰甲基-烷基氨基]乙酸，淀粉样β蛋白水解中胰岛素降解酶的底物依赖性调节剂。
Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-β hydrolysis.
作者信息
Charton Julie, Gauriot Marion, Guo Qing, Hennuyer Nathalie, Marechal Xavier, Dumont Julie, Hamdane Malika, Pottiez Virginie, Landry Valerie, Sperandio Olivier, Flipo Marion, Buee Luc, Staels Bart, Leroux Florence, Tang Wei-Jen, Deprez Benoit, Deprez-Poulain Rebecca
机构信息
INSERM U761 Biostructures and Drug Discovery, Lille, France; Univ Lille Nord de France, Lille F-59000, France; Institut Pasteur de Lille, IFR 142, Lille F-59000, France; PRIM, Lille F-59000, France; CDithem Platform/IGM, Paris, France.
Ben-May Institute for Cancer Research, The University of Chicago, W421 Chicago, IL, USA.
出版信息
Eur J Med Chem. 2014 May 22;79:184-93. doi: 10.1016/j.ejmech.2014.04.009. Epub 2014 Apr 4.
Insulin degrading enzyme (IDE) is a highly conserved zinc metalloprotease that is involved in the clearance of various physiologically peptides like amyloid-beta and insulin. This enzyme has been involved in the physiopathology of diabetes and Alzheimer's disease. We describe here a series of small molecules discovered by screening. Co-crystallization of the compounds with IDE revealed a binding both at the permanent exosite and at the discontinuous, conformational catalytic site. Preliminary structure-activity relationships are described. Selective inhibition of amyloid-beta degradation over insulin hydrolysis was possible. Neuroblastoma cells treated with the optimized compound display a dose-dependent increase in amyloid-beta levels.
胰岛素降解酶（IDE）是一种高度保守的锌金属蛋白酶，参与清除多种生理肽，如β-淀粉样蛋白和胰岛素。这种酶与糖尿病和阿尔茨海默病的病理生理过程有关。我们在此描述了通过筛选发现的一系列小分子。这些化合物与IDE的共结晶显示它们在永久性外部位点和不连续的构象催化位点均有结合。描述了初步的构效关系。实现了对β-淀粉样蛋白降解的选择性抑制，而不是胰岛素水解。用优化后的化合物处理神经母细胞瘤细胞后，β-淀粉样蛋白水平呈剂量依赖性增加。
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