A Hot‐Segment‐Based Approach for the Design of Cross‐Amyloid Interaction Surface Mimics as Inhibitors of Amyloid Self‐Assembly |
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| Authors: | Dr Erika Andreetto Dipl‐Chem Eleni Malideli Dr Li‐Mei Yan Dipl‐Ing Michael Kracklauer MSc Karine Farbiarz Dipl‐Chem Marianna Tatarek‐Nossol Prof Dr Gerhard Rammes M Sc Elke Prade Tatjana Neumüller Dr Andrea Caporale M Sc Anna Spanopoulou B Sc Maria Bakou Prof Dr Bernd Reif Prof Dr Aphrodite Kapurniotu |
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| Institution: | 1. Division of Peptide Biochemistry, Technische Universit?t München, Emil‐Erlenmeyer‐Forum 5, 85354 Freising (Germany);2. Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Aachen (Germany);3. Department of Anesthesiology, Technische Universit?t München/Klinikum Rechts der Isar, München (Germany);4. Department of Chemistry, Technische Universit?t München, Garching (Germany);5. Helmholtz Zentrum Muenchen (HMGU), Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg (Germany) |
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| Abstract: | The design of inhibitors of protein–protein interactions mediating amyloid self‐assembly is a major challenge mainly due to the dynamic nature of the involved structures and interfaces. Interactions of amyloidogenic polypeptides with other proteins are important modulators of self‐assembly. Here we present a hot‐segment‐linking approach to design a series of mimics of the IAPP cross‐amyloid interaction surface with Aβ (ISMs) as nanomolar inhibitors of amyloidogenesis and cytotoxicity of Aβ, IAPP, or both polypeptides. The nature of the linker determines ISM structure and inhibitory function including both potency and target selectivity. Importantly, ISMs effectively suppress both self‐ and cross‐seeded IAPP self‐assembly. Our results provide a novel class of highly potent peptide leads for targeting protein aggregation in Alzheimer’s disease, type 2 diabetes, or both diseases and a chemical approach to inhibit amyloid self‐assembly and pathogenic interactions of other proteins as well. |
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| Keywords: | Alzheimer’ s disease amyloid inhibitors islet amyloid polypeptide protein– protein interactions β ‐amyloid peptide |
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