NDLI: Structural Design, Solid-Phase Synthesis and Activity of Membrane-Anchored β-Secretase Inhibitors on Aβ Generation from Wild-Type and Swedish-Mutant APP

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Structural Design, Solid-Phase Synthesis and Activity of Membrane-Anchored β-Secretase Inhibitors on Aβ Generation from Wild-Type and Swedish-Mutant APP

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Structural Design, Solid-Phase Synthesis and Activity of Membrane-Anchored β-Secretase Inhibitors on Aβ Generation from Wild-Type and Swedish-Mutant APP

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Linning, Philipp Weidlich, Sebastian Schlechtingen, Georg Klafki, Hans-wolfgang Gruner, Margit Wiltfang, Jens Knölker, Hans-joachim Schieb, Heinke Jennings, Gary
Description	Author Affiliation: Schieb H ( Department of Psychiatry and Psychotherapy, University of Duisburg-Essen, LVR-Klinikum, Essen, Germany.)
Abstract	Covalent coupling of β-secretase inhibitors to a raftophilic lipid anchor via a suitable spacer by using solid-phase peptide synthesis leads to tripartite structures displaying substantially improved inhibition of cellular secretion of the β-amyloid peptide (Aβ). Herein, we describe a series of novel tripartite structures, their full characterization by NMR spectroscopy and mass spectrometry, and the analysis of their biological activity in cell-based assays. The tripartite structure concept is applicable to different pharmacophores, and the potency in terms of β-secretase inhibition can be optimized by adjusting the spacer length to achieve an optimal distance of the inhibitor from the lipid bilayer. A tripartite structure containing a transition-state mimic inhibitor was found to be less potent on Aβ generation from Swedish-mutant amyloid precursor protein (APP) than from the wild-type protein. Moreover, our observations suggest that specific variants of Aβ are generated from wild-type APP but not from Swedish-mutant APP and are resistant to β-secretase inhibition. Efficient inhibition of Aβ secretion by tripartite structures in the absence of appreciable neurotoxicity was confirmed in a primary neuronal cell culture, thus further supporting the concept.
ISSN	09476539
e-ISSN	15213765
Journal	Chemistry - A European Journal
Issue Number	48
Volume Number	16
Language	English
Publisher	Wiley-VCH;ChemPubSoc Europe
Publisher Date	2010-12-27
Publisher Place	Germany
Access Restriction	Open
Subject Keyword	Amyloid Precursor Protein Secretases Antagonists & Inhibitors Amyloid Beta-Peptides Secretion Amyloid Beta-Protein Precursor Metabolism Cell Membrane Drug Effects Alzheimer Disease Drug Therapy Amino Acid Sequence Genetics Animals Aspartic Acid Chemistry Aspartic Acid Endopeptidases Enzymology Dose-Response Relationship, Drug Molecular Structure Nuclear Magnetic Resonance, Biomolecular Sequence Homology, Amino Acid Research Support, Non-U.S. Gov't
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Catalysis

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