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@ARTICLE{Hornung:277879,
      author       = {Hornung, Simon and Vogl, Dominik P and Naltsas, Denise and
                      Volta, Beatrice Dalla and Ballmann, Markus and Marcon,
                      Beatrice and Syed, Muhammed Muazzam Kamil and Wu, Yiyang and
                      Spanopoulou, Anna and Feederle, Regina and Heidrich, Luzia
                      and Bernhagen, Jürgen and Koeglsperger, Thomas and
                      Höglinger, Günter U and Rammes, Gerhard and Lashuel, Hilal
                      A and Kapurniotu, Aphrodite},
      title        = {{M}ulti-{T}argeting {M}acrocyclic {P}eptides as {N}anomolar
                      {I}nhibitors of {S}elf- and {C}ross-{S}eeded {A}myloid
                      {S}elf-{A}ssembly of α-{S}ynuclein.},
      journal      = {Angewandte Chemie / International edition},
      volume       = {64},
      number       = {14},
      issn         = {1433-7851},
      address      = {Weinheim},
      publisher    = {Wiley-VCH},
      reportid     = {DZNE-2025-00499},
      pages        = {e202422834},
      year         = {2025},
      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.},
      keywords     = {alpha-Synuclein: metabolism / alpha-Synuclein: chemistry /
                      alpha-Synuclein: antagonists $\&$ inhibitors / Humans /
                      Amyloid: metabolism / Amyloid: antagonists $\&$ inhibitors /
                      Amyloid: chemistry / Islet Amyloid Polypeptide: metabolism /
                      Islet Amyloid Polypeptide: chemistry / Amyloid
                      beta-Peptides: metabolism / Amyloid beta-Peptides: chemistry
                      / Amyloid beta-Peptides: antagonists $\&$ inhibitors /
                      Macrocyclic Compounds: chemistry / Macrocyclic Compounds:
                      pharmacology / Peptides: chemistry / Peptides: pharmacology
                      / (cross-)seeding (Other) / amyloid inhibitor (Other) /
                      protein-protein interactions (Other) / self-assembly (Other)
                      / α-synuclein (Other) / alpha-Synuclein (NLM Chemicals) /
                      Amyloid (NLM Chemicals) / Islet Amyloid Polypeptide (NLM
                      Chemicals) / Amyloid beta-Peptides (NLM Chemicals) /
                      Macrocyclic Compounds (NLM Chemicals) / Peptides (NLM
                      Chemicals)},
      cin          = {AG Herms / AG Feederle / Clinical Research (Munich)},
      ddc          = {540},
      cid          = {I:(DE-2719)1110001 / I:(DE-2719)1140004 /
                      I:(DE-2719)1111015},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 353 - Clinical and
                      Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39822034},
      doi          = {10.1002/anie.202422834},
      url          = {https://pub.dzne.de/record/277879},
}