Journal Article

DZNE-2025-00499

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Multi-Targeting Macrocyclic Peptides as Nanomolar Inhibitors of Self- and Cross-Seeded Amyloid Self-Assembly of α-Synuclein.

Hornung, S. ; Vogl, D. P. ; Naltsas, D. ; Volta, B. D. ; Ballmann, M. ; Marcon, B. ; Syed, M. M. K. ; Wu, Y.DZNE* ; Spanopoulou, A. ; Feederle, R.DZNE* ; Heidrich, L. ; Bernhagen, J. ; Koeglsperger, T.DZNE* ; Höglinger, G. U.DZNE* ; Rammes, G. ; Lashuel, H. A. ; Kapurniotu, A.

2025
Wiley-VCH Weinheim

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Please use a persistent id in citations: doi:10.1002/anie.202422834

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.

Keyword(s): alpha-Synuclein: metabolism (MeSH) ; alpha-Synuclein: chemistry (MeSH) ; alpha-Synuclein: antagonists & inhibitors (MeSH) ; Humans (MeSH) ; Amyloid: metabolism (MeSH) ; Amyloid: antagonists & inhibitors (MeSH) ; Amyloid: chemistry (MeSH) ; Islet Amyloid Polypeptide: metabolism (MeSH) ; Islet Amyloid Polypeptide: chemistry (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Amyloid beta-Peptides: chemistry (MeSH) ; Amyloid beta-Peptides: antagonists & inhibitors (MeSH) ; Macrocyclic Compounds: chemistry (MeSH) ; Macrocyclic Compounds: pharmacology (MeSH) ; Peptides: chemistry (MeSH) ; Peptides: pharmacology (MeSH) ; (cross-)seeding ; amyloid inhibitor ; protein-protein interactions ; self-assembly ; α-synuclein ; alpha-Synuclein ; Amyloid ; Islet Amyloid Polypeptide ; Amyloid beta-Peptides ; Macrocyclic Compounds ; Peptides

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Contributing Institute(s):

1. Translational Brain Research (AG Herms)
2. Antibody Production (AG Feederle)
3. Clinical Research (Munich) (Clinical Research (Munich))

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2025

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Database coverage:
; ; ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; Index Chemicus ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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