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

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 and Aphrodite Kapurniotu ()
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Karin Taş: Technical University of Munich (TUM)
Beatrice Dalla Volta: Technical University of Munich (TUM)
Christina Lindner: Technical University of Munich (TUM)
Omar El Bounkari: Klinikum der Universität München, Ludwig-Maximilian-University (LMU)
Kathleen Hille: Technical University of Munich (TUM)
Yuan Tian: Klinikum der Universität München, Ludwig-Maximilian-University (LMU)
Xènia Puig-Bosch: Technical University of Munich/Klinikum Rechts der Isar
Markus Ballmann: Technical University of Munich/Klinikum Rechts der Isar
Simon Hornung: Technical University of Munich (TUM)
Martin Ortner: Technical University of Munich (TUM)
Sophia Prem: Technical University of Munich (TUM)
Laura Meier: Technical University of Munich
Gerhard Rammes: Technical University of Munich/Klinikum Rechts der Isar
Martin Haslbeck: Technical University of Munich
Christian Weber: Klinikum der Universität München, Ludwig-Maximilian-University Munich (LMU)
Remco T. A. Megens: Klinikum der Universität München, Ludwig-Maximilian-University Munich (LMU)
Jürgen Bernhagen: Klinikum der Universität München, Ludwig-Maximilian-University (LMU)
Aphrodite Kapurniotu: Technical University of Munich (TUM)

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: Abstract 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32688-0

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DOI: 10.1038/s41467-022-32688-0

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