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@ARTICLE{Deike:889722,
author = {Deike, Stefanie and Rothemund, Sven and Voigt, Bruno and
Samantray, Suman and Strodel, Birgit and Binder, Wolfgang
H.},
title = {β-{T}urn mimetic synthetic peptides as amyloid-β
aggregation inhibitors},
journal = {Bioorganic chemistry},
volume = {101},
issn = {0045-2068},
address = {San Diego, Calif.},
publisher = {Elsevier},
reportid = {FZJ-2021-00344},
pages = {104012 -},
year = {2020},
abstract = {Aggregation of amyloid peptides results in severe
neurodegenerative diseases. While the fibril structures of
Aβ40and Aβ42 have been described recently, resolution of
the aggregation pathway and evaluation of potent
inhibitorsstill remains elusive, in particular in view of
the hairpin-region of Aβ40. We here report the
preparationof beta-turn mimetic conjugates containing
synthetic turn mimetic structures in the turn region of
Aβ40 and Aβ16-35, replacing 2 amino acids in the
turn-region G25 – K28. The structure of the turn mimic
induces both, accelerationof fibrillation and the complete
inhibition of fibrillation, confirming the importance of the
turn regionon the aggregation. Replacing position G25-S26
provided the best inhibition effect for both beta-turn
mimetics,the bicyclic BTD 1 and the aromatic TAA 2, while
positions N27-K28 and V24-G25 showed only weaker or
noinhibitory effects. When comparing different turn mimetics
at the same position (G25-S26), conjugate 1a bearingthe BTD
turn showed the best inhibition of Aβ40 aggregation, while
5-amino-valeric acid 4a showed the weakesteffect. Thus there
is a pronounced impact on fibrillation with the chemical
nature of the embedded beta-turnmimic:the conformationally
constrained turns 1 and 2 lead to a significantly reduced
fibrillation, even inhibitingfibrillation of native Aβ40
when added in amounts down to 1/10, whereas the more
flexible beta-turn-mimics 4-amino-benzoic acid 3a and
5-amino-valeric acid 4a lead to enhanced fibrillation.
Toxicity-testing of the mostsuccessful conjugate showed only
minor toxicity in cell-viability assays using the N2a cell
line. Structuraldownsizing lead to the short fragment
BTD/peptide Aβ16-35 as inhibitor of the aggregation of
Aβ40, opening largepotential for further small peptide
based inhibitors.},
cin = {IBI-7},
ddc = {540},
cid = {I:(DE-Juel1)IBI-7-20200312},
pnm = {553 - Physical Basis of Diseases (POF3-553)},
pid = {G:(DE-HGF)POF3-553},
typ = {PUB:(DE-HGF)16},
pubmed = {32683138},
UT = {WOS:000552635800006},
doi = {10.1016/j.bioorg.2020.104012},
url = {https://juser.fz-juelich.de/record/889722},
}