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000277879 1001_ $$aHornung, Simon$$b0
000277879 245__ $$aMulti-Targeting Macrocyclic Peptides as Nanomolar Inhibitors of Self- and Cross-Seeded Amyloid Self-Assembly of α-Synuclein.
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000277879 520__ $$aAmyloid 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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000277879 650_7 $$2Other$$a(cross-)seeding
000277879 650_7 $$2Other$$aamyloid inhibitor
000277879 650_7 $$2Other$$aprotein-protein interactions
000277879 650_7 $$2Other$$aself-assembly
000277879 650_7 $$2Other$$aα-synuclein
000277879 650_7 $$2NLM Chemicals$$aalpha-Synuclein
000277879 650_7 $$2NLM Chemicals$$aAmyloid
000277879 650_7 $$2NLM Chemicals$$aIslet Amyloid Polypeptide
000277879 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000277879 650_7 $$2NLM Chemicals$$aMacrocyclic Compounds
000277879 650_7 $$2NLM Chemicals$$aPeptides
000277879 650_2 $$2MeSH$$aalpha-Synuclein: metabolism
000277879 650_2 $$2MeSH$$aalpha-Synuclein: chemistry
000277879 650_2 $$2MeSH$$aalpha-Synuclein: antagonists & inhibitors
000277879 650_2 $$2MeSH$$aHumans
000277879 650_2 $$2MeSH$$aAmyloid: metabolism
000277879 650_2 $$2MeSH$$aAmyloid: antagonists & inhibitors
000277879 650_2 $$2MeSH$$aAmyloid: chemistry
000277879 650_2 $$2MeSH$$aIslet Amyloid Polypeptide: metabolism
000277879 650_2 $$2MeSH$$aIslet Amyloid Polypeptide: chemistry
000277879 650_2 $$2MeSH$$aAmyloid beta-Peptides: metabolism
000277879 650_2 $$2MeSH$$aAmyloid beta-Peptides: chemistry
000277879 650_2 $$2MeSH$$aAmyloid beta-Peptides: antagonists & inhibitors
000277879 650_2 $$2MeSH$$aMacrocyclic Compounds: chemistry
000277879 650_2 $$2MeSH$$aMacrocyclic Compounds: pharmacology
000277879 650_2 $$2MeSH$$aPeptides: chemistry
000277879 650_2 $$2MeSH$$aPeptides: pharmacology
000277879 7001_ $$aVogl, Dominik P$$b1
000277879 7001_ $$aNaltsas, Denise$$b2
000277879 7001_ $$aVolta, Beatrice Dalla$$b3
000277879 7001_ $$aBallmann, Markus$$b4
000277879 7001_ $$aMarcon, Beatrice$$b5
000277879 7001_ $$aSyed, Muhammed Muazzam Kamil$$b6
000277879 7001_ $$0P:(DE-2719)9002415$$aWu, Yiyang$$b7$$udzne
000277879 7001_ $$aSpanopoulou, Anna$$b8
000277879 7001_ $$0P:(DE-2719)2812867$$aFeederle, Regina$$b9$$udzne
000277879 7001_ $$aHeidrich, Luzia$$b10
000277879 7001_ $$aBernhagen, Jürgen$$b11
000277879 7001_ $$0P:(DE-2719)2810825$$aKoeglsperger, Thomas$$b12$$udzne
000277879 7001_ $$0P:(DE-2719)2811373$$aHöglinger, Günter U$$b13$$udzne
000277879 7001_ $$aRammes, Gerhard$$b14
000277879 7001_ $$aLashuel, Hilal A$$b15
000277879 7001_ $$00000-0001-6124-7232$$aKapurniotu, Aphrodite$$b16
000277879 773__ $$0PERI:(DE-600)2011836-3$$a10.1002/anie.202422834$$gVol. 64, no. 14, p. e202422834$$n14$$pe202422834$$tAngewandte Chemie / International edition$$v64$$x1433-7851$$y2025
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