Efficient inhibition of the Alzheimer's disease β-secretase by membrane targeting
Efficient inhibition of the Alzheimer's disease β-secretase by membrane targeting
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DOI：
10.1126/science.1156609
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发表时间：
2008-04-25
期刊：
影响因子：
56.9
通讯作者：
Simons, Kai
中科院分区：
文献类型：
--
作者：
Rajendran, Lawrence;Schneider, Anja;Simons, Kai
β-分泌酶在β-淀粉样蛋白形成中起关键作用，因此为阿尔茨海默病提供了治疗靶点。抑制剂的设计通常集中在活性位点的结合上，而忽略了活性酶的亚细胞定位.我们已经解决了这个问题，通过合成一种膜锚定的β-分泌酶过渡态抑制剂，将其连接到甾醇部分。因此，我们将抑制剂靶向于内体中发现的活性β-分泌酶，并且还降低了抑制剂的维度，增加了其局部膜浓度。这种抑制剂降低酶活性更有效地比自由抑制剂在培养的细胞和体内。除了有效地靶向β-分泌酶外，这种策略还可以用于设计针对其他膜蛋白靶点的强效药物。
beta-secretase plays a critical role in beta- amyloid formation and thus provides a therapeutic target for Alzheimer's disease. Inhibitor design has usually focused on active- site binding, neglecting the subcellular localization of active enzyme. We have addressed this issue by synthesizing a membrane- anchored version of a beta- secretase transition- state inhibitor by linking it to a sterol moiety. Thus, we targeted the inhibitor to active beta- secretase found in endosomes and also reduced the dimensionality of the inhibitor, increasing its local membrane concentration. This inhibitor reduced enzyme activity much more efficiently than did the free inhibitor in cultured cells and in vivo. In addition to effectively targeting beta- secretase, this strategy could also be used in designing potent drugs against other membrane protein targets.