Rzepecki, Petra; Nagel-Steger, Luitgard; Feuerstein, Sophie; Linne, Uwe; Molt, Oliver; Zadmard, Reza; Aschermann, Katja; Wehner, Markus; Schrader, Thomas; Riesner, Detlev:

Prevention of Alzheimer's Disease-associated Ab Aggregation by Rationally Designed Nonpeptidic b-Sheet Ligands.

In: Journal of Biological Chemistry (J.Biol.Chem.), Jg. 279 (2004) ; Nr. 46, S. 47497-47505
ISSN: 0021-9258
Zeitschriftenaufsatz / Fach: Chemie
Abstract:
A new concept is introduced for the rational design of b-sheet ligands, which prevent protein aggregation. Oligomeric acylated aminopyrazoles with a donor-acceptor-donor (DAD) hydrogen bond pattern complementary to that of a b-sheet efficiently block the solvent-exposed b-sheet portions in Ab-(1-40) and thereby prevent formation of insol. protein aggregates. D. gradient centrifugation revealed that in the initial phase, the size of Ab aggregates was efficiently kept between the trimeric and 15-meric state, whereas after 5 days an addnl. high mol. wt. 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 min. energy conformations showed a perfect complementarity to a b-sheet. The concn. dependence of the inhibitory effect of a trimeric aminopyrazole deriv. allowed an estn. of the dissocn. const. in the range of 10-5 M. Finally, electrospray ionization mass spectrometry (ESI-MS) was used to det. the aggregation kinetics of Ab-(1-40) in the absence and in the presence of the ligands. From the comparable decrease in Ab monomer concn., we conclude that these b-sheet ligands do not prevent the initial oligomerization of monomeric Ab but rather block further aggregation of spontaneously formed small oligomers. Together with the results from d. gradient centrifugation and fluorescence correlation spectroscopy it is now possible to restrict the approx. size of sol. Ab aggregates formed in the presence of both inhibitors from 3- to 15-mers.