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| 001 | 16633 | ||
| 005 | 20200402210044.0 | ||
| 024 | 7 | _ | |2 pmid |a pmid:21381732 |
| 024 | 7 | _ | |2 DOI |a 10.1021/ja107675n |
| 024 | 7 | _ | |2 WOS |a WOS:000291715300041 |
| 037 | _ | _ | |a PreJuSER-16633 |
| 041 | _ | _ | |a eng |
| 082 | _ | _ | |a 540 |
| 084 | _ | _ | |2 WoS |a Chemistry, Multidisciplinary |
| 100 | 1 | _ | |0 P:(DE-HGF)0 |a Hochdörffer, K. |b 0 |
| 245 | _ | _ | |a Rational Design of ß-Sheet Ligands Against Aß(42)-Induced Toxicity |
| 260 | _ | _ | |a Washington, DC |b American Chemical Society |c 2011 |
| 300 | _ | _ | |a 4348 - 4358 |
| 336 | 7 | _ | |a Journal Article |0 PUB:(DE-HGF)16 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a article |2 DRIVER |
| 440 | _ | 0 | |0 8502 |a Journal of the American Chemical Society |v 133 |x 0002-7863 |y 12 |
| 500 | _ | _ | |3 POF3_Assignment on 2016-02-29 |
| 500 | _ | _ | |a 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. |
| 520 | _ | _ | |a 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. |
| 536 | _ | _ | |0 G:(DE-Juel1)FUEK409 |2 G:(DE-HGF) |a Funktion und Dysfunktion des Nervensystems |c P33 |x 0 |
| 536 | _ | _ | |0 G:(DE-Juel1)FUEK505 |2 G:(DE-HGF) |a BioSoft: Makromolekulare Systeme und biologische Informationsverarbeitung |c P45 |x 1 |
| 588 | _ | _ | |a Dataset connected to Web of Science, Pubmed |
| 650 | _ | 2 | |2 MeSH |a Amyloid beta-Peptides: antagonists & inhibitors |
| 650 | _ | 2 | |2 MeSH |a Amyloid beta-Peptides: toxicity |
| 650 | _ | 2 | |2 MeSH |a Binding Sites: drug effects |
| 650 | _ | 2 | |2 MeSH |a Ligands |
| 650 | _ | 2 | |2 MeSH |a Models, Molecular |
| 650 | _ | 2 | |2 MeSH |a Molecular Structure |
| 650 | _ | 2 | |2 MeSH |a Peptide Fragments: antagonists & inhibitors |
| 650 | _ | 2 | |2 MeSH |a Peptide Fragments: toxicity |
| 650 | _ | 2 | |2 MeSH |a Protein Structure, Secondary |
| 650 | _ | 2 | |2 MeSH |a Pyrazoles: chemical synthesis |
| 650 | _ | 2 | |2 MeSH |a Pyrazoles: chemistry |
| 650 | _ | 2 | |2 MeSH |a Pyrazoles: pharmacology |
| 650 | _ | 2 | |2 MeSH |a Structure-Activity Relationship |
| 650 | _ | 7 | |0 0 |2 NLM Chemicals |a Amyloid beta-Peptides |
| 650 | _ | 7 | |0 0 |2 NLM Chemicals |a Ligands |
| 650 | _ | 7 | |0 0 |2 NLM Chemicals |a Peptide Fragments |
| 650 | _ | 7 | |0 0 |2 NLM Chemicals |a Pyrazoles |
| 650 | _ | 7 | |0 0 |2 NLM Chemicals |a amyloid beta-protein (1-42) |
| 650 | _ | 7 | |2 WoSType |a J |
| 700 | 1 | _ | |0 P:(DE-HGF)0 |a März-Berberich, J. |b 1 |
| 700 | 1 | _ | |0 P:(DE-Juel1)VDB72731 |a Nagel-Steger, L. |b 2 |u FZJ |
| 700 | 1 | _ | |0 P:(DE-HGF)0 |a Epple, M. |b 3 |
| 700 | 1 | _ | |0 P:(DE-Juel1)VDB92200 |a Meyer-Zaika, W. |b 4 |u FZJ |
| 700 | 1 | _ | |0 P:(DE-Juel1)VDB101167 |a Horn, A.H. |b 5 |u FZJ |
| 700 | 1 | _ | |0 P:(DE-Juel1)VDB55200 |a Sticht, H. |b 6 |u FZJ |
| 700 | 1 | _ | |0 P:(DE-Juel1)VDB2074 |a Sinha, S. |b 7 |u FZJ |
| 700 | 1 | _ | |0 P:(DE-Juel1)VDB101168 |a Bitan, G. |b 8 |u FZJ |
| 700 | 1 | _ | |0 P:(DE-Juel1)VDB77919 |a Schrader, T. |b 9 |u FZJ |
| 773 | _ | _ | |0 PERI:(DE-600)1472210-0 |a 10.1021/ja107675n |g Vol. 133, p. 4348 - 4358 |p 4348 - 4358 |q 133<4348 - 4358 |t Journal of the American Chemical Society |v 133 |x 0002-7863 |y 2011 |
| 856 | 7 | _ | |u http://dx.doi.org/10.1021/ja107675n |
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| 913 | 2 | _ | |a DE-HGF |b Key Technologies |l BioSoft – Fundamentals for future Technologies in the fields of Soft Matter and Life Sciences |1 G:(DE-HGF)POF3-550 |0 G:(DE-HGF)POF3-559H |2 G:(DE-HGF)POF3-500 |v Addenda |x 0 |
| 914 | 1 | _ | |y 2011 |
| 915 | _ | _ | |0 StatID:(DE-HGF)0010 |a JCR/ISI refereed |
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| 980 | _ | _ | |a UNRESTRICTED |
| 981 | _ | _ | |a I:(DE-Juel1)IBI-7-20200312 |
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