TY  - JOUR
AU  - Hornung, Simon
AU  - Vogl, Dominik P
AU  - Naltsas, Denise
AU  - Volta, Beatrice Dalla
AU  - Ballmann, Markus
AU  - Marcon, Beatrice
AU  - Syed, Muhammed Muazzam Kamil
AU  - Wu, Yiyang
AU  - Spanopoulou, Anna
AU  - Feederle, Regina
AU  - Heidrich, Luzia
AU  - Bernhagen, Jürgen
AU  - Koeglsperger, Thomas
AU  - Höglinger, Günter U
AU  - Rammes, Gerhard
AU  - Lashuel, Hilal A
AU  - Kapurniotu, Aphrodite
TI  - Multi-Targeting Macrocyclic Peptides as Nanomolar Inhibitors of Self- and Cross-Seeded Amyloid Self-Assembly of α-Synuclein.
JO  - Angewandte Chemie / International edition
VL  - 64
IS  - 14
SN  - 1433-7851
CY  - Weinheim
PB  - Wiley-VCH
M1  - DZNE-2025-00499
SP  - e202422834
PY  - 2025
AB  - 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.
KW  - alpha-Synuclein: metabolism
KW  - alpha-Synuclein: chemistry
KW  - alpha-Synuclein: antagonists & inhibitors
KW  - Humans
KW  - Amyloid: metabolism
KW  - Amyloid: antagonists & inhibitors
KW  - Amyloid: chemistry
KW  - Islet Amyloid Polypeptide: metabolism
KW  - Islet Amyloid Polypeptide: chemistry
KW  - Amyloid beta-Peptides: metabolism
KW  - Amyloid beta-Peptides: chemistry
KW  - Amyloid beta-Peptides: antagonists & inhibitors
KW  - Macrocyclic Compounds: chemistry
KW  - Macrocyclic Compounds: pharmacology
KW  - Peptides: chemistry
KW  - Peptides: pharmacology
KW  - (cross-)seeding (Other)
KW  - amyloid inhibitor (Other)
KW  - protein-protein interactions (Other)
KW  - self-assembly (Other)
KW  - α-synuclein (Other)
KW  - alpha-Synuclein (NLM Chemicals)
KW  - Amyloid (NLM Chemicals)
KW  - Islet Amyloid Polypeptide (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Macrocyclic Compounds (NLM Chemicals)
KW  - Peptides (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39822034
DO  - DOI:10.1002/anie.202422834
UR  - https://pub.dzne.de/record/277879
ER  -