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@ARTICLE{Rzepecki:836463,
      author       = {Rzepecki, P. and Nagel-Steger, Luitgard and Feuerstein,
                      Sophie and Linne, U. and Molt, O. and Zadmard, R. and
                      Aschermann, K. and Wehner, M. and Schrader, T. and Riesner,
                      D.},
      title        = {{P}revention of {A}lzheimer's disease-associated {A}beta
                      aggregation by rationally designed nonpeptidic beta-sheet
                      ligands.},
      journal      = {The journal of biological chemistry},
      volume       = {279},
      issn         = {0021-9258},
      address      = {Bethesda, Md.},
      publisher    = {Soc.},
      reportid     = {FZJ-2017-05581},
      pages        = {47497-47505},
      year         = {2004},
      abstract     = {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.},
      cin          = {ICS-6},
      ddc          = {570},
      cid          = {I:(DE-Juel1)ICS-6-20110106},
      pnm          = {553 - Physical Basis of Diseases (POF3-553)},
      pid          = {G:(DE-HGF)POF3-553},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000224957000012},
      pubmed       = {pmid:15322133},
      doi          = {10.1074/jbc.M405914200},
      url          = {https://juser.fz-juelich.de/record/836463},
}