Designed peptides as nanomolar cross-amyloid inhibitors acting via supramolecular nanofiber co-assembly.
Nat Commun. 2022 Aug 25;13(1):5004. doi: 10.1038/s41467-022-32688-0. PMID: 36008417; PMCID: PMC9411207.
|Authors/Editors:||Taş K, Volta BD, Lindner C, El Bounkari O, Hille K, Tian Y, Puig-Bosch X, Ballmann M, Hornung S, Ortner M, Prem S, Meier L, Rammes G, Haslbeck M, Weber C, Megens RTA, Bernhagen J, Kapurniotu A.|
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.