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


Rajendran, L; Schneider, A; Schlechtingen, G; Weidlich, S; Ries, J; Braxmeier, T; Schwille, P; Schulz, J B; Schroeder, C; Simons, M; Jennings, G; Knölker, H J; Simons, K (2008). Efficient inhibition of the Alzheimer's disease beta-secretase by membrane targeting. Science, 320(5875):520-523.

Abstract

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.

Abstract

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute for Regenerative Medicine (IREM)
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2008
Deposited On:09 Sep 2011 14:33
Last Modified:16 Aug 2016 10:13
Publisher:American Association for the Advancement of Science (AAAS)
ISSN:0036-8075
Publisher DOI:https://doi.org/10.1126/science.1156609
PubMed ID:18436784

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