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| Home > Publications Database > Multi-Targeting Macrocyclic Peptides as Nanomolar Inhibitors of Self- and Cross-Seeded Amyloid Self-Assembly of α-Synuclein. > print |
| 001 | 277879 | ||
| 005 | 20250427001146.0 | ||
| 024 | 7 | _ | |a 10.1002/anie.202422834 |2 doi |
| 024 | 7 | _ | |a pmid:39822034 |2 pmid |
| 024 | 7 | _ | |a 1433-7851 |2 ISSN |
| 024 | 7 | _ | |a 0570-0833 |2 ISSN |
| 024 | 7 | _ | |a 1521-3773 |2 ISSN |
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| 037 | _ | _ | |a DZNE-2025-00499 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 540 |
| 100 | 1 | _ | |a Hornung, Simon |b 0 |
| 245 | _ | _ | |a Multi-Targeting Macrocyclic Peptides as Nanomolar Inhibitors of Self- and Cross-Seeded Amyloid Self-Assembly of α-Synuclein. |
| 260 | _ | _ | |a Weinheim |c 2025 |b Wiley-VCH |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1745402198_31858 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a 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. |
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| 650 | _ | 7 | |a (cross-)seeding |2 Other |
| 650 | _ | 7 | |a amyloid inhibitor |2 Other |
| 650 | _ | 7 | |a protein-protein interactions |2 Other |
| 650 | _ | 7 | |a self-assembly |2 Other |
| 650 | _ | 7 | |a α-synuclein |2 Other |
| 650 | _ | 7 | |a alpha-Synuclein |2 NLM Chemicals |
| 650 | _ | 7 | |a Amyloid |2 NLM Chemicals |
| 650 | _ | 7 | |a Islet Amyloid Polypeptide |2 NLM Chemicals |
| 650 | _ | 7 | |a Amyloid beta-Peptides |2 NLM Chemicals |
| 650 | _ | 7 | |a Macrocyclic Compounds |2 NLM Chemicals |
| 650 | _ | 7 | |a Peptides |2 NLM Chemicals |
| 650 | _ | 2 | |a alpha-Synuclein: metabolism |2 MeSH |
| 650 | _ | 2 | |a alpha-Synuclein: chemistry |2 MeSH |
| 650 | _ | 2 | |a alpha-Synuclein: antagonists & inhibitors |2 MeSH |
| 650 | _ | 2 | |a Humans |2 MeSH |
| 650 | _ | 2 | |a Amyloid: metabolism |2 MeSH |
| 650 | _ | 2 | |a Amyloid: antagonists & inhibitors |2 MeSH |
| 650 | _ | 2 | |a Amyloid: chemistry |2 MeSH |
| 650 | _ | 2 | |a Islet Amyloid Polypeptide: metabolism |2 MeSH |
| 650 | _ | 2 | |a Islet Amyloid Polypeptide: chemistry |2 MeSH |
| 650 | _ | 2 | |a Amyloid beta-Peptides: metabolism |2 MeSH |
| 650 | _ | 2 | |a Amyloid beta-Peptides: chemistry |2 MeSH |
| 650 | _ | 2 | |a Amyloid beta-Peptides: antagonists & inhibitors |2 MeSH |
| 650 | _ | 2 | |a Macrocyclic Compounds: chemistry |2 MeSH |
| 650 | _ | 2 | |a Macrocyclic Compounds: pharmacology |2 MeSH |
| 650 | _ | 2 | |a Peptides: chemistry |2 MeSH |
| 650 | _ | 2 | |a Peptides: pharmacology |2 MeSH |
| 700 | 1 | _ | |a Vogl, Dominik P |b 1 |
| 700 | 1 | _ | |a Naltsas, Denise |b 2 |
| 700 | 1 | _ | |a Volta, Beatrice Dalla |b 3 |
| 700 | 1 | _ | |a Ballmann, Markus |b 4 |
| 700 | 1 | _ | |a Marcon, Beatrice |b 5 |
| 700 | 1 | _ | |a Syed, Muhammed Muazzam Kamil |b 6 |
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| 700 | 1 | _ | |a Höglinger, Günter U |0 P:(DE-2719)2811373 |b 13 |u dzne |
| 700 | 1 | _ | |a Rammes, Gerhard |b 14 |
| 700 | 1 | _ | |a Lashuel, Hilal A |b 15 |
| 700 | 1 | _ | |a Kapurniotu, Aphrodite |0 0000-0001-6124-7232 |b 16 |
| 773 | _ | _ | |a 10.1002/anie.202422834 |g Vol. 64, no. 14, p. e202422834 |0 PERI:(DE-600)2011836-3 |n 14 |p e202422834 |t Angewandte Chemie / International edition |v 64 |y 2025 |x 1433-7851 |
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