Multi‐Targeting Macrocyclic Peptides as Nanomolar Inhibitors of Self‐ and Cross‐Seeded Amyloid Self‐Assembly of α‐Synuclein

Hornung, Simon; Vogl, Dominik P.; Naltsas, Denise; Volta, Beatrice Dalla; Ballmann, Markus; Marcon, Beatrice; Syed, Muhammed Muazzam Kamil; Wu, Yiyang; Spanopoulou, Anna; Feederle, Regina ; Heidrich, Luzia; Bernhagen, Jürgen ; Koeglsperger, Thomas ; Höglinger, Günter U. ; Rammes, Gerhard; Lashuel, Hilal A. und Kapurniotu, Aphrodite (2025): Multi‐Targeting Macrocyclic Peptides as Nanomolar Inhibitors of Self‐ and Cross‐Seeded Amyloid Self‐Assembly of α‐Synuclein. In: Angewandte Chemie International Edition, Vol. 64, No. 14, e202422834

Abstract

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.

• Item Type: Journal article
• Faculties: Medicine > Munich Cluster for Systems Neurology (SyNergy); Medicine > Institute for Stroke and Dementia Research (ISD); Medicine > Medical Center of the University of Munich > Neurological Clinic and Polyclinic with Friedrich Baur Institute
• Research Centers: Munich Center for Neurosciences – Brain & Mind
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 1433-7851
• Language: English
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198