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Rajendran, L., Schneider, A., Schlechtingen, G., Weidlich, S., Ries, J., Braxmeier, T., Schwille, P., Schulz, J.B., Schroeder, C., Simons, M., Jennings, G., Kn√∂lker, H.J., Simons, K. (2008). Efficient inhibition of the Alzheimer's disease beta-secretase by membrane targeting.  Science 320(5875): 520--523.
FlyBase ID
FBrf0204630
Publication Type
Research paper
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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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Science
    Title
    Science
    Publication Year
    1895-
    ISBN/ISSN
    0036-8075 1095-9203
    Data From Reference
    Alleles (4)
    Genes (4)
    Human Disease Models (3)
    Transgenic Constructs (4)