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@ARTICLE{Hochdrffer:16633,
      author       = {Hochdörffer, K. and März-Berberich, J. and Nagel-Steger,
                      L. and Epple, M. and Meyer-Zaika, W. and Horn, A.H. and
                      Sticht, H. and Sinha, S. and Bitan, G. and Schrader, T.},
      title        = {{R}ational {D}esign of ß-{S}heet {L}igands {A}gainst
                      {A}ß(42)-{I}nduced {T}oxicity},
      journal      = {Journal of the American Chemical Society},
      volume       = {133},
      issn         = {0002-7863},
      address      = {Washington, DC},
      publisher    = {American Chemical Society},
      reportid     = {PreJuSER-16633},
      pages        = {4348 - 4358},
      year         = {2011},
      note         = {Financial support from the American Health Assistance
                      Foundation (grant A2008-350) and the UCLA Jim Easton
                      Consortium for Alzheimer's Drug Discovery and Biomarker
                      Development is gratefully acknowledged. This work was also
                      supported by the Deutsche Forschungsgemeinschaft and the
                      Volkswagen foundation.},
      abstract     = {A β-sheet-binding scaffold was equipped with long-range
                      chemical groups for tertiary contacts toward specific
                      regions of the Alzheimer's Aβ fibril. The new constructs
                      contain a trimeric aminopyrazole carboxylic acid, elongated
                      with a C-terminal binding site, whose influence on the
                      aggregation behavior of the Aβ(42) peptide was studied. MD
                      simulations after trimer docking to the anchor point
                      (F19/F20) suggest distinct groups of complex structures each
                      of which featured additional specific interactions with
                      characteristic Aβ regions. Members of each group also
                      displayed a characteristic pattern in their
                      antiaggregational behavior toward Aβ. Specifically, remote
                      lipophilic moieties such as a dodecyl, cyclohexyl, or LPFFD
                      fragment can form dispersive interactions with the nonpolar
                      cluster of amino acids between I31 and V36. They were shown
                      to strongly reduce Thioflavine T (ThT) fluorescence and
                      protect cells from Aβ lesions (MTT viability assays).
                      Surprisingly, very thick fibrils and a high β-sheet content
                      were detected in transmission electron microscopy (TEM) and
                      CD spectroscopic experiments. On the other hand, distant
                      single or multiple lysines which interact with the ladder of
                      stacked E22 residues found in Aβ fibrils completely
                      dissolve existing β-sheets (ThT, CD) and lead to
                      unstructured, nontoxic material (TEM, MTT). Finally, the
                      triethyleneglycol spacer between heterocyclic β-sheet
                      ligand and appendix was found to play an active role in
                      destabilizing the turn of the U-shaped protofilament.
                      Fluorescence correlation spectroscopy (FCS) and
                      sedimentation velocity analysis (SVA) provided experimental
                      evidence for some smaller benign aggregates of very thin,
                      delicate structure (TEM, MTT). A detailed investigation by
                      dynamic light scattering (DLS) and other methods proved that
                      none of the new ligands acts as a colloid. The evolving
                      picture for the disaggregation mechanism by these new hybrid
                      ligands implies transformation of well-ordered fibrils into
                      less structured aggregates with a high molecular weight. In
                      the few cases where fibrillar components remain, these
                      display a significantly altered morphology and have lost
                      their acute cellular toxicity.},
      keywords     = {Amyloid beta-Peptides: antagonists $\&$ inhibitors /
                      Amyloid beta-Peptides: toxicity / Binding Sites: drug
                      effects / Ligands / Models, Molecular / Molecular Structure
                      / Peptide Fragments: antagonists $\&$ inhibitors / Peptide
                      Fragments: toxicity / Protein Structure, Secondary /
                      Pyrazoles: chemical synthesis / Pyrazoles: chemistry /
                      Pyrazoles: pharmacology / Structure-Activity Relationship /
                      Amyloid beta-Peptides (NLM Chemicals) / Ligands (NLM
                      Chemicals) / Peptide Fragments (NLM Chemicals) / Pyrazoles
                      (NLM Chemicals) / amyloid beta-protein (1-42) (NLM
                      Chemicals) / J (WoSType)},
      cin          = {ICS-6},
      ddc          = {540},
      cid          = {I:(DE-Juel1)ICS-6-20110106},
      pnm          = {Funktion und Dysfunktion des Nervensystems / BioSoft:
                      Makromolekulare Systeme und biologische
                      Informationsverarbeitung},
      pid          = {G:(DE-Juel1)FUEK409 / G:(DE-Juel1)FUEK505},
      shelfmark    = {Chemistry, Multidisciplinary},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:21381732},
      UT           = {WOS:000291715300041},
      doi          = {10.1021/ja107675n},
      url          = {https://juser.fz-juelich.de/record/16633},
}