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, Aphrodite Kapurniotu

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish
Article number5004
JournalNature Communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

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