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Designed peptides as nanomolar cross-amyloid inhibitors acting via supramolecular nanofiber co-assembly

Amyloid self-assembly is linked to numerous devastating cell-degenerative diseases. However, designing inhibitors of this pathogenic process remains a major challenge. Cross-interactions between amyloid-β peptide (Aβ) and islet amyloid polypeptide (IAPP), key polypeptides of Alzheimer’s disease (AD)...

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Main Authors: Taş, Karin (Author) , Volta, Beatrice Dalla (Author) , Lindner, Christina (Author) , El Bounkari, Omar (Author) , Hille, Kathleen (Author) , Tian, Yuan (Author) , Puig-Bosch, Xènia (Author) , Ballmann, Markus (Author) , Hornung, Simon (Author) , Ortner, Martin (Author) , Prem, Sophia (Author) , Meier, Laura (Author) , Rammes, Gerhard (Author) , Haslbeck, Martin (Author) , Weber, Christian (Author) , Megens, Remco T. A. (Author) , Bernhagen, Jürgen (Author) , Kapurniotu, Aphrodite (Author)
Format: Article (Journal)
Language:English
Published: 25 August 2022
In: Nature Communications
Year: 2022, Volume: 13, Pages: 1-22
ISSN:2041-1723
DOI:10.1038/s41467-022-32688-0
Online Access:Resolving-System, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41467-022-32688-0
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41467-022-32688-0
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Author Notes:Karin Taş, Beatrice Dalla Volta, Christina Lindner, Omar El Bounkari, Kathleen Hille, Yuan Tian, Xènia Puig-Bosch, Markus Ballmann, Simon Hornung, Martin Ortner, Sophia Prem, Laura Meier, Gerhard Rammes, Martin Haslbeck, Christian Weber, Remco T.A. Megens, Jürgen Bernhagen & Aphrodite Kapurniotu
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Summary:Amyloid self-assembly is linked to numerous devastating cell-degenerative diseases. However, designing inhibitors of this pathogenic process remains a major challenge. Cross-interactions between amyloid-β peptide (Aβ) and islet amyloid polypeptide (IAPP), key polypeptides of Alzheimer’s disease (AD) and type 2 diabetes (T2D), have been suggested to link AD with T2D pathogenesis. Here, we show that constrained peptides designed to mimic the Aβ amyloid core (ACMs) are nanomolar cross-amyloid inhibitors of both IAPP and Aβ42 and effectively suppress reciprocal cross-seeding. Remarkably, ACMs act by co-assembling with IAPP or Aβ42 into amyloid fibril-resembling but non-toxic nanofibers and their highly ordered superstructures. Co-assembled nanofibers exhibit various potentially beneficial features including thermolability, proteolytic degradability, and effective cellular clearance which are reminiscent of labile/reversible functional amyloids. ACMs are thus promising leads for potent anti-amyloid drugs in both T2D and AD while the supramolecular nanofiber co-assemblies should inform the design of novel functional (hetero-)amyloid-based nanomaterials for biomedical/biotechnological applications.
Item Description:Gesehen am 20.12.2022
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-022-32688-0

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