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

Tas, Karin; Dalla Volta, Beatrice; Lindner, Christina; El Bounkari, Omar; Hille, Kathleen; Tian, Yuan; Puig-Bosch, Xenia; Ballmann, Markus; Hornung, Simon; Ortner, Martin; Prem, Sophia; Meier, Laura; Rammes, Gerhard; Haslbeck, Martin; Weber, Christian; Megens, Remco T. A.; Bernhagen, Juergen und Kapurniotu, Aphrodite (2022): Designed peptides as nanomolar cross-amyloid inhibitors acting via supramolecular nanofiber co-assembly. In: Nature Communications, Bd. 13, Nr. 1, 5004

Abstract

Amyloid self-assembly is linked to type 2 diabetes and Alzheimer's disease. Here the authors designed constrained peptides which are nanomolar amyloid inhibitors of the key polypeptides IAPP and A beta 42 and act 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-beta peptide (A beta) 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 A beta amyloid core (ACMs) are nanomolar cross-amyloid inhibitors of both IAPP and A beta 42 and effectively suppress reciprocal cross-seeding. Remarkably, ACMs act by co-assembling with IAPP or A beta 42 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 201302640
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198