%0 Journal Article
%A Hornung, Simon
%A Vogl, Dominik P
%A Naltsas, Denise
%A Volta, Beatrice Dalla
%A Ballmann, Markus
%A Marcon, Beatrice
%A Syed, Muhammed Muazzam Kamil
%A Wu, Yiyang
%A Spanopoulou, Anna
%A Feederle, Regina
%A Heidrich, Luzia
%A Bernhagen, Jürgen
%A Koeglsperger, Thomas
%A Höglinger, Günter U
%A Rammes, Gerhard
%A Lashuel, Hilal A
%A Kapurniotu, Aphrodite
%T Multi-Targeting Macrocyclic Peptides as Nanomolar Inhibitors of Self- and Cross-Seeded Amyloid Self-Assembly of α-Synuclein.
%J Angewandte Chemie / International edition
%V 64
%N 14
%@ 1433-7851
%C Weinheim
%I Wiley-VCH
%M DZNE-2025-00499
%P e202422834
%D 2025
%X Amyloid self-assembly of α-synuclein (αSyn) is linked to the pathogenesis of Parkinson's disease (PD). Type 2 diabetes (T2D) has recently emerged as a risk factor for PD. Cross-interactions between their amyloidogenic proteins may act as molecular links. In fact, fibrils of islet amyloid polypeptide (IAPP) (T2D) can cross-seed αSyn amyloidogenesis and αSyn and IAPP colocalize in PD brains. Inhibition of both self- and IAPP-cross-seeded αSyn amyloidogenesis could thus interfere with PD pathogenesis. Here we show that macrocyclic peptides, designed to mimic IAPP self-/cross-interaction sites and previously found to inhibit amyloidogenesis of IAPP and/or Alzheimer's disease (AD) amyloid-β peptide Aβ40(42), are nanomolar inhibitors of both self- and IAPP-cross-seeded amyloid self-assembly of αSyn. Anti-amyloid function is mediated by nanomolar affinity interactions with αSyn via three αSyn regions which are identified as key sites of both αSyn self-assembly and its cross-interactions with IAPP. We also show that the peptides block Aβ42-mediated cross-seeding of αSyn as well. Based on their broad spectrum anti-amyloid function and additional drug-like features, these peptides are leads for multifunctional anti-amyloid drugs in PD, T2D, AD, and their comorbidities, while the identified αSyn key segments are valuable targets for novel, multi-site targeting amyloid inhibitors in PD and related synucleinopathies.
%K alpha-Synuclein: metabolism
%K alpha-Synuclein: chemistry
%K alpha-Synuclein: antagonists & inhibitors
%K Humans
%K Amyloid: metabolism
%K Amyloid: antagonists & inhibitors
%K Amyloid: chemistry
%K Islet Amyloid Polypeptide: metabolism
%K Islet Amyloid Polypeptide: chemistry
%K Amyloid beta-Peptides: metabolism
%K Amyloid beta-Peptides: chemistry
%K Amyloid beta-Peptides: antagonists & inhibitors
%K Macrocyclic Compounds: chemistry
%K Macrocyclic Compounds: pharmacology
%K Peptides: chemistry
%K Peptides: pharmacology
%K (cross-)seeding (Other)
%K amyloid inhibitor (Other)
%K protein-protein interactions (Other)
%K self-assembly (Other)
%K α-synuclein (Other)
%K alpha-Synuclein (NLM Chemicals)
%K Amyloid (NLM Chemicals)
%K Islet Amyloid Polypeptide (NLM Chemicals)
%K Amyloid beta-Peptides (NLM Chemicals)
%K Macrocyclic Compounds (NLM Chemicals)
%K Peptides (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:39822034
%R 10.1002/anie.202422834
%U https://pub.dzne.de/record/277879