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| 001 | 836463 | ||
| 005 | 20210129231010.0 | ||
| 024 | 7 | _ | |a 10.1074/jbc.M405914200 |2 doi |
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| 037 | _ | _ | |a FZJ-2017-05581 |
| 082 | _ | _ | |a 570 |
| 100 | 1 | _ | |0 P:(DE-HGF)0 |a Rzepecki, P. |b 0 |
| 245 | _ | _ | |a Prevention of Alzheimer's disease-associated Abeta aggregation by rationally designed nonpeptidic beta-sheet ligands. |
| 260 | _ | _ | |a Bethesda, Md. |b Soc. |c 2004 |
| 336 | 7 | _ | |2 DRIVER |a article |
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| 336 | 7 | _ | |0 PUB:(DE-HGF)16 |2 PUB:(DE-HGF) |a Journal Article |b journal |m journal |s 1502201548_1184 |
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| 520 | _ | _ | |a A new concept is introduced for the rational design of β-sheet ligands, which prevent protein aggregation. Oligomeric acylated aminopyrazoles with a donor-acceptor-donor (DAD) hydrogen bond pattern complementary to that of a β-sheet efficiently block the solvent-exposed β-sheet portions in Aβ-(1–40) and thereby prevent formation of insoluble protein aggregates. Density gradient centrifugation revealed that in the initial phase, the size of Aβ aggregates was efficiently kept between the trimeric and 15-meric state, whereas after 5 days an additional high molecular weight fraction appeared. With fluorescence correlation spectroscopy (FCS) exactly those two, i.e. a dimeric aminopyrazole with an oxalyl spacer and a trimeric head-to-tail connected aminopyrazole, of nine similar aminopyrazole ligands were identified as efficient aggregation retardants whose minimum energy conformations showed a perfect complementarity to a β-sheet. The concentration dependence of the inhibitory effect of a trimeric aminopyrazole derivative allowed an estimation of the dissociation constant in the range of 10–5 m. Finally, electrospray ionization mass spectrometry (ESI-MS) was used to determine the aggregation kinetics of Aβ-(1–40) in the absence and in the presence of the ligands. From the comparable decrease in Aβ monomer concentration, we conclude that these β-sheet ligands do not prevent the initial oligomerization of monomeric Aβ but rather block further aggregation of spontaneously formed small oligomers. Together with the results from density gradient centrifugation and fluorescence correlation spectroscopy it is now possible to restrict the approximate size of soluble Aβ aggregates formed in the presence of both inhibitors from 3- to 15-mers. |
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| 700 | 1 | _ | |0 P:(DE-Juel1)162443 |a Nagel-Steger, Luitgard |b 1 |
| 700 | 1 | _ | |0 P:(DE-Juel1)162167 |a Feuerstein, Sophie |b 2 |
| 700 | 1 | _ | |0 P:(DE-HGF)0 |a Linne, U. |b 3 |
| 700 | 1 | _ | |0 P:(DE-HGF)0 |a Molt, O. |b 4 |
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| 700 | 1 | _ | |0 P:(DE-HGF)0 |a Schrader, T. |b 8 |e Corresponding author |
| 700 | 1 | _ | |0 P:(DE-HGF)0 |a Riesner, D. |b 9 |
| 773 | _ | _ | |0 PERI:(DE-600)1474604-9 |a 10.1074/jbc.M405914200 |p 47497-47505 |t The journal of biological chemistry |v 279 |x 0021-9258 |y 2004 |
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