title: Efficient inhibition of the Alzheimer's disease beta-secretase by membrane targeting.
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.
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstr. 108, 01307 Dresden, Germany.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Rajendran
authors.forename: Anja
authors.initials: A
authors.lastname: Schneider
authors.forename: Georg
authors.initials: G
authors.lastname: Schlechtingen
authors.forename: Sebastian
authors.initials: S
authors.lastname: Weidlich
authors.forename: Jonas
authors.initials: J
authors.lastname: Ries
authors.forename: Tobias
authors.initials: T
authors.lastname: Braxmeier
authors.forename: Petra
authors.initials: P
authors.lastname: Schwille
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Schulz
authors.forename: Cornelia
authors.initials: C
authors.lastname: Schroeder
authors.forename: Mikael
authors.initials: M
authors.lastname: Simons
authors.forename: Gary
authors.initials: G
authors.lastname: Jennings
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Knölker
authors.forename: Kai
authors.initials: K
authors.lastname: Simons
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D004330:Drosophila / Q000235:genetics; D016503:Drug Delivery Systems; D015195:Drug Design; D004705:Endocytosis; D011992:Endosomes / Q000201:enzymology*; D006367:HeLa Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D021962:Membrane Microdomains / Q000201:enzymology; D051379:Mice; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013261:Sterols
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010455:Peptides; D011480:Protease Inhibitors; D013261:Sterols; D053829:Amyloid Precursor Protein Secretases