Efficient inhibition of the Alzheimer's disease β-secretase by membrane targeting

被引：213

作者：

Rajendran, Lawrence ^{[1
]}

Schneider, Anja ^{[2
]}

Schlechtingen, Georg ^{[3
,4
]}

Weidlich, Sebastian ^{[4
]}

Ries, Jonas ^{[5
]}

Braxmeier, Tobias ^{[3
,4
]}

Schwille, Petra ^{[5
]}

Schulz, Joerg B. ^{[6
]}

Schroeder, Cornelia ^{[4
]}

Simons, Mikael ^{[2
]}

Jennings, Gary ^{[3
]}

Knoelker, Hans-Joachim ^{[3
,4
]}

Simons, Kai ^{[1
]}

机构：

[1] Max Planck Inst Mol Cell Biol & Genet, D-01307 Dresden, Germany

[2] Max Planck Inst Expt Med, D-37075 Gottingen, Germany

[3] JADO Technol GmbH, D-01307 Dresden, Germany

[4] Tech Univ Dresden, Dept Chem, D-01069 Dresden, Germany

[5] Biotec, Biotechnol Zentrum, D-01307 Dresden, Germany

[6] Ctr Neurol Med, D-37073 Gottingen, Germany

来源：

SCIENCE | 2008年 / 320卷 / 5875期

关键词：

D O I：

10.1126/science.1156609

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：520 / 523

页数：4

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