Effect of Helical Conformation and Side-Chain Structure on y-Secretase Inhibition by β-Peptide Foldamers : Insight into Substrate Recognition
Effect of Helical Conformation and Side-Chain Structure on y-Secretase Inhibition by β-Peptide Foldamers : Insight into Substrate Recognition
复制标题
螺旋构象和侧链结构对 β-肽折叠体抑制 y-分泌酶的影响：深入了解底物识别
DOI：
10.1021/jm301306c
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发表时间：
2013
期刊：
影响因子：
7.3
通讯作者：
Tsunehiko Higuchi
中科院分区：
文献类型：
--
作者：
Yuki Imamura;Naoki Umezawa;Satoko Osawa;Naoaki Shimada;Takuya Higo;Satoshi Yokoshima;Tohru Fukuyama;Takeshi Iwatsubo;Nobuki Kato;Taisuke Tomita;Tsunehiko Higuchi
底物选择性抑制或调节γ-分泌酶的活性可能是预防和治疗阿尔茨海默病的有效策略。γ-分泌酶负责淀粉样蛋白-β肽的产生。我们已经证明，螺旋β-肽折叠蛋白是γ-分泌酶的有效和特异性抑制剂。在这里，我们报告了利用光亲和探针识别文件夹的目标位点。光探针直接特异地标记了早老素1的n端片段，预测了其初始底物对接位点的位置。我们还通过制备各种衍生物来优化折叠体结构，并通过在母体结构中加入亲水性和中性官能团获得了两种高效折叠体。侧链官能团的种类和结合的位置对γ-分泌酶抑制活性都很重要。抑制活性的底物选择性对所含侧链基团的种类也相当敏感。
Substrate-selective inhibition or modulation of the activity of γ-secretase, which is responsible for the generation of amyloid-β peptides, might be an effective strategy for prevention and treatment of Alzheimer’s disease. We have shown that helical β-peptide foldamers are potent and specific inhibitors of γ-secretase. Here we report identification of target site of the foldamers by using a photoaffinity probe. The photoprobe directly and specifically labeled the N-terminal fragment of presenilin 1, in which the initial substrate docking site is predicted to be located. We also optimized the foldamer structure by preparing a variety of derivatives and obtained two highly potent foldamers by incorporation of a hydrophilic and neutral functional group into the parent structure. The class of side chain functional group and the position of incorporation were both important for γ-secretase-inhibitory activity. The substrate selectivity of the inhibitory activity was also quite sensitive to the class of side chain group incorporated.