Binding of TCA to the prion protein: mechanism, implication for therapy, and application as probe for complex formation of bio-macromolecules.

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.

Cite this paper

@article{Mangels2009BindingOT, title={Binding of TCA to the prion protein: mechanism, implication for therapy, and application as probe for complex formation of bio-macromolecules.}, author={Christian Mangels and Andreas O. Frank and Jan Ziegler and R. James Klingenstein and Kristian Schweimer and Dieter Willbold and Carsten Korth and Paul R{\"{o}sch and Stephan Schwarzinger}, journal={Journal of biomolecular structure & dynamics}, year={2009}, volume={27 2}, pages={163-70} }