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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

Authors

  • Heinke Schieb,

    1. Department of Psychiatry and Psychotherapy, University of Duisburg-Essen, LVR-Klinikum, Essen (Germany)
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  • Dr. Sebastian Weidlich,

    1. Department of Chemistry, Technische Universität Dresden, Bergstrasse 66, 01069 Dresden (Germany), Fax: (+49) 351-463-37030
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  • Dr. Georg Schlechtingen,

    1. Department of Chemistry, Technische Universität Dresden, Bergstrasse 66, 01069 Dresden (Germany), Fax: (+49) 351-463-37030
    2. JADO Technologies GmbH, Tatzberg 47–51, 01307 Dresden (Germany)
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  • Philipp Linning,

    1. Department of Chemistry, Technische Universität Dresden, Bergstrasse 66, 01069 Dresden (Germany), Fax: (+49) 351-463-37030
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  • Dr. Gary Jennings,

    1. JADO Technologies GmbH, Tatzberg 47–51, 01307 Dresden (Germany)
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  • Dr. Margit Gruner,

    1. Department of Chemistry, Technische Universität Dresden, Bergstrasse 66, 01069 Dresden (Germany), Fax: (+49) 351-463-37030
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  • Prof. Dr. Jens Wiltfang,

    1. Department of Psychiatry and Psychotherapy, University of Duisburg-Essen, LVR-Klinikum, Essen (Germany)
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  • Dr. Hans-Wolfgang Klafki,

    Corresponding author
    1. Department of Psychiatry and Psychotherapy, University of Duisburg-Essen, LVR-Klinikum, Essen (Germany)
    • Department of Psychiatry and Psychotherapy, University of Duisburg-Essen, LVR-Klinikum, Essen (Germany)
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  • Prof. Dr. Hans-Joachim Knölker

    Corresponding author
    1. Department of Chemistry, Technische Universität Dresden, Bergstrasse 66, 01069 Dresden (Germany), Fax: (+49) 351-463-37030
    2. JADO Technologies GmbH, Tatzberg 47–51, 01307 Dresden (Germany)
    • Department of Chemistry, Technische Universität Dresden, Bergstrasse 66, 01069 Dresden (Germany), Fax: (+49) 351-463-37030
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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.

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