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          Institute: MPI für molekulare Zellbiologie und Genetik     Collection: Publikationen MPI-CBG 2008     Display Documents



ID: 414318.0, MPI für molekulare Zellbiologie und Genetik / Publikationen MPI-CBG 2008
Efficient inhibition of the Alzheimer's disease beta-secretase by membrane targeting
Authors:Rajendran, Lawrence; Schneider, Anja; Schlechtingen, Georg; Weidlich, Sebastian; Ries, Jonas; Braxmeier, Tobias; Schwille, Petra; Schulz, Jorg B; Schroeder, Cornelia; Simons, Mikael; Jennings, Gary; Knolker, Hans-Joachim; Simons, Kai
Date of Publication (YYYY-MM-DD):2008
Title of Journal:Science
Volume:320
Issue / Number:5875
Start Page:520
End Page:523
Copyright:not available
Audience:Experts Only
Intended Educational Use:No
Abstract / Description: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.
External Publication Status:published
Document Type:Article
Communicated by:n.n.
Affiliations:MPI f�r molekulare Zellbiologie und Genetik
Identifiers:LOCALID:977
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