强效膜天冬氨酸蛋白酶2（β-分泌酶）抑制剂：设计、合成、蛋白质-配体X射线结构及体内评估
Potent memapsin 2 (beta-secretase) inhibitors: design, synthesis, protein-ligand X-ray structure, and in vivo evaluation.
作者信息
Ghosh Arun K, Kumaragurubaran Nagaswamy, Hong Lin, Kulkarni Sarang, Xu Xiaoming, Miller Heather B, Reddy Dandepally Srinivasa, Weerasena Vajira, Turner Robert, Chang Wanpin, Koelsch Gerald, Tang Jordan
机构信息
Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
出版信息
Bioorg Med Chem Lett. 2008 Feb 1;18(3):1031-6. doi: 10.1016/j.bmcl.2007.12.028. Epub 2008 Jan 3.
Abstract
Structure-based design, synthesis, and biological evaluation of a series of peptidomimetic beta-secretase inhibitors incorporating hydroxyethylamine isosteres are described. We have identified inhibitor 24 which has shown exceedingly potent activity in memapsin 2 enzyme inhibitory (K(i) 1.8 nM) and cellular (IC(50)=1 nM in Chinese hamster ovary cells) assays. Inhibitor 24 has also shown very impressive in vivo properties (up to 65% reduction of plasma A beta) in transgenic mice. The X-ray structure of protein-ligand complex of memapsin 2 revealed critical interactions in the memapsin 2 active site.
摘要
本文描述了一系列包含羟乙胺等排体的拟肽β-分泌酶抑制剂的基于结构的设计、合成及生物学评价。我们已鉴定出抑制剂24，它在β-分泌酶2（memapsin 2）酶抑制试验（K(i)为1.8 nM）和细胞试验（在中国仓鼠卵巢细胞中的IC(50) = 1 nM）中显示出极其强效的活性。抑制剂24在转基因小鼠中也表现出非常令人印象深刻的体内特性（血浆β-淀粉样蛋白最多降低65%）。β-分泌酶2的蛋白质-配体复合物的X射线结构揭示了其活性位点中的关键相互作用。
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