TY  - JOUR
AU  - Hochdörffer, K.
AU  - März-Berberich, J.
AU  - Nagel-Steger, L.
AU  - Epple, M.
AU  - Meyer-Zaika, W.
AU  - Horn, A.H.
AU  - Sticht, H.
AU  - Sinha, S.
AU  - Bitan, G.
AU  - Schrader, T.
TI  - Rational Design of ß-Sheet Ligands Against Aß(42)-Induced Toxicity
JO  - Journal of the American Chemical Society
VL  - 133
SN  - 0002-7863
CY  - Washington, DC
PB  - American Chemical Society
M1  - PreJuSER-16633
SP  - 4348 - 4358
PY  - 2011
N1  - 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.
AB  - 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.
KW  - Amyloid beta-Peptides: antagonists & inhibitors
KW  - Amyloid beta-Peptides: toxicity
KW  - Binding Sites: drug effects
KW  - Ligands
KW  - Models, Molecular
KW  - Molecular Structure
KW  - Peptide Fragments: antagonists & inhibitors
KW  - Peptide Fragments: toxicity
KW  - Protein Structure, Secondary
KW  - Pyrazoles: chemical synthesis
KW  - Pyrazoles: chemistry
KW  - Pyrazoles: pharmacology
KW  - Structure-Activity Relationship
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Ligands (NLM Chemicals)
KW  - Peptide Fragments (NLM Chemicals)
KW  - Pyrazoles (NLM Chemicals)
KW  - amyloid beta-protein (1-42) (NLM Chemicals)
KW  - J (WoSType)
LB  - PUB:(DE-HGF)16
C6  - pmid:21381732
UR  - <Go to ISI:>//WOS:000291715300041
DO  - DOI:10.1021/ja107675n
UR  - https://juser.fz-juelich.de/record/16633
ER  -