Potent memapsin 2 (β-secretase) inhibitors:: Design, synthesis, protein-ligand X-ray structure, and in vivo evaluation
Potent memapsin 2 (β-secretase) inhibitors:: Design, synthesis, protein-ligand X-ray structure, and in vivo evaluation
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DOI：
10.1016/j.bmcl.2007.12.028
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发表时间：
2008-02-01
影响因子：
2.7
通讯作者：
Tang, Jordan
中科院分区：
文献类型：
--
作者：
Ghosh, Arun K.;Kumaragurubarana, Nagaswamy;Tang, Jordan
本文描述了一系列含有羟乙胺同分异构体的拟肽p分泌酶抑制剂的结构设计、合成和生物学评价。我们已经鉴定出抑制因子24在膜蛋白酶2酶抑制（K-i 1.8 nM）和细胞（IC50 = 1 nM在中国仓鼠卵巢细胞）实验中表现出非常强的活性。抑制剂24在转基因小鼠中也显示出非常令人印象深刻的体内特性（高达65%的血浆A β减少）。memapsin 2蛋白-配体复合物的x射线结构揭示了memapsin 2活性位点的关键相互作用。(C) 2007 Elsevier Ltd.版权所有。
Structure-based design, synthesis, and biological evaluation of a series of peptidomimetic P-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 (IC50 = 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. (C) 2007 Elsevier Ltd. All rights reserved.