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Mangels, Christian ; Frank, Andreas ; Ziegler, Jan ; Klingenstein, R. ; Schweimer, Kristian ; Willbold, Dieter ; Korth, Carsten ; Rösch, Paul ; Schwarzinger, Stephan:
Binding of TCA to the Prion Protein : Mechanism, Implication for Therapy, and Application as Probe for Complex Formation of Bio-macromolecules.
In: Journal of Biomolecular Structure & Dynamics.
Bd. 27
(2009)
Heft 2
.
- S. 163-170.
ISSN 1538-0254
DOI: https://doi.org/10.1080/07391102.2009.10507306
Abstract
Tricyclic aromatic compounds (TCA) are promising candidates for treatment of transmissible spongiform encephalopathies. Direct binding to the cellular prion protein (PrP(C)) has been proposed as anti-prion active mechanism. We here show by means of NMR-spectroscopy that binding of TCA occurs with millimolar affinity to motifs consisting of two neighboring aromatic residues (Ar-Ar motif). It is independent of the secondary structure of this motif and of the side chain attached to the TCA and it is not specific to PrP(C). Because biologically inactive 9-aminoacridine (9-aa) binds with similar K(D) as anti-prion active quinacrine, direct interaction with PrP(C) as mechanism of action appears highly unlikely. However, binding of 9-aa to Ar-Ar-motifs in proteins can be used as reporter for biological macromolecule interactions, by measuring changes in T(1)-NMR relaxation times of 9-aa.