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Open Access Green as soon as Postprint is submitted to ZB.
A hot-segment-based approach for the design of cross-amyloid interaction surface mimics as inhibitors of amyloid self-assembly.
Angew. Chem.-Int. Edit. 54, 13095-13100 (2015)
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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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Alzheimer’s Disease ; Amyloid Inhibitors ; Islet Amyloid Polypeptide ; Protein-protein Interactions ; β-amyloid Peptide
ISSN (print) / ISBN
1433-7851
e-ISSN
1521-3773
Quellenangaben
Volume: 54,
Issue: 44,
Pages: 13095-13100
Publisher
Wiley
Publishing Place
Weinheim
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Structural Biology (STB)