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000016633 0247_ $$2pmid$$apmid:21381732
000016633 0247_ $$2DOI$$a10.1021/ja107675n
000016633 0247_ $$2WOS$$aWOS:000291715300041
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000016633 084__ $$2WoS$$aChemistry, Multidisciplinary
000016633 1001_ $$0P:(DE-HGF)0$$aHochdörffer, K.$$b0
000016633 245__ $$aRational Design of ß-Sheet Ligands Against Aß(42)-Induced Toxicity
000016633 260__ $$aWashington, DC$$bAmerican Chemical Society$$c2011
000016633 300__ $$a4348 - 4358
000016633 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article
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000016633 3367_ $$2BibTeX$$aARTICLE
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000016633 440_0 $$08502$$aJournal of the American Chemical Society$$v133$$x0002-7863$$y12
000016633 500__ $$3POF3_Assignment on 2016-02-29
000016633 500__ $$aFinancial 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.
000016633 520__ $$aA 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.
000016633 536__ $$0G:(DE-Juel1)FUEK409$$2G:(DE-HGF)$$aFunktion und Dysfunktion des Nervensystems$$cP33$$x0
000016633 536__ $$0G:(DE-Juel1)FUEK505$$2G:(DE-HGF)$$aBioSoft: Makromolekulare Systeme und biologische Informationsverarbeitung$$cP45$$x1
000016633 588__ $$aDataset connected to Web of Science, Pubmed
000016633 650_2 $$2MeSH$$aAmyloid beta-Peptides: antagonists & inhibitors
000016633 650_2 $$2MeSH$$aAmyloid beta-Peptides: toxicity
000016633 650_2 $$2MeSH$$aBinding Sites: drug effects
000016633 650_2 $$2MeSH$$aLigands
000016633 650_2 $$2MeSH$$aModels, Molecular
000016633 650_2 $$2MeSH$$aMolecular Structure
000016633 650_2 $$2MeSH$$aPeptide Fragments: antagonists & inhibitors
000016633 650_2 $$2MeSH$$aPeptide Fragments: toxicity
000016633 650_2 $$2MeSH$$aProtein Structure, Secondary
000016633 650_2 $$2MeSH$$aPyrazoles: chemical synthesis
000016633 650_2 $$2MeSH$$aPyrazoles: chemistry
000016633 650_2 $$2MeSH$$aPyrazoles: pharmacology
000016633 650_2 $$2MeSH$$aStructure-Activity Relationship
000016633 650_7 $$00$$2NLM Chemicals$$aAmyloid beta-Peptides
000016633 650_7 $$00$$2NLM Chemicals$$aLigands
000016633 650_7 $$00$$2NLM Chemicals$$aPeptide Fragments
000016633 650_7 $$00$$2NLM Chemicals$$aPyrazoles
000016633 650_7 $$00$$2NLM Chemicals$$aamyloid beta-protein (1-42)
000016633 650_7 $$2WoSType$$aJ
000016633 7001_ $$0P:(DE-HGF)0$$aMärz-Berberich, J.$$b1
000016633 7001_ $$0P:(DE-Juel1)VDB72731$$aNagel-Steger, L.$$b2$$uFZJ
000016633 7001_ $$0P:(DE-HGF)0$$aEpple, M.$$b3
000016633 7001_ $$0P:(DE-Juel1)VDB92200$$aMeyer-Zaika, W.$$b4$$uFZJ
000016633 7001_ $$0P:(DE-Juel1)VDB101167$$aHorn, A.H.$$b5$$uFZJ
000016633 7001_ $$0P:(DE-Juel1)VDB55200$$aSticht, H.$$b6$$uFZJ
000016633 7001_ $$0P:(DE-Juel1)VDB2074$$aSinha, S.$$b7$$uFZJ
000016633 7001_ $$0P:(DE-Juel1)VDB101168$$aBitan, G.$$b8$$uFZJ
000016633 7001_ $$0P:(DE-Juel1)VDB77919$$aSchrader, T.$$b9$$uFZJ
000016633 773__ $$0PERI:(DE-600)1472210-0$$a10.1021/ja107675n$$gVol. 133, p. 4348 - 4358$$p4348 - 4358$$q133<4348 - 4358$$tJournal of the American Chemical Society$$v133$$x0002-7863$$y2011
000016633 8567_ $$uhttp://dx.doi.org/10.1021/ja107675n
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000016633 915__ $$0StatID:(DE-HGF)0010$$aJCR/ISI refereed
000016633 9141_ $$y2011
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000016633 9131_ $$0G:(DE-Juel1)FUEK505$$aDE-HGF$$bSchlüsseltechnologien$$kP45$$lBiologische Informationsverarbeitung$$vBioSoft: Makromolekulare Systeme und biologische Informationsverarbeitung$$x1
000016633 9132_ $$0G:(DE-HGF)POF3-559H$$1G:(DE-HGF)POF3-550$$2G:(DE-HGF)POF3-500$$aDE-HGF$$bKey Technologies$$lBioSoft – Fundamentals for future Technologies in the fields of Soft Matter and Life Sciences$$vAddenda$$x0
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