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J. Biol. Chem., Vol. 279, Issue 46, 47497-47505, November 12, 2004

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Prevention of Alzheimer's Disease-associated A Aggregation by Rationally Designed Nonpeptidic -Sheet Ligands^*

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

From the Department of Chemistry, Philipps-Universität Marburg, Hans-Meerwein-Strasse, 35032 Marburg, and the ^¶Institute of Physical Biology and Biological-Medical Research Center, Heinrich-Heine Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany

A new concept is introduced for the rational design of -sheet ligands, which prevent protein aggregation. Oligomeric acylated aminopyrazoles with a donor-acceptor-donor (DAD) hydrogen bond pattern complementary to that of a -sheet efficiently block the solvent-exposed -sheet portions in A-(1–40) and thereby prevent formation of insoluble protein aggregates. Density gradient centrifugation revealed that in the initial phase, the size of A 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 -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 A-(1–40) in the absence and in the presence of the ligands. From the comparable decrease in A monomer concentration, we conclude that these -sheet ligands do not prevent the initial oligomerization of monomeric A 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 A aggregates formed in the presence of both inhibitors from 3- to 15-mers.

Received for publication, May 27, 2004 , and in revised form, August 16, 2004.

^* This work was supported by the Volkswagenstiftung (priority area of conformational control of biomolecular functions). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed. Tel.: 49-6421-282-5544; Fax: 49-6421-282-8917; E-mail: schradet{at}mailer.unimarburg.de.

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