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Mangels C, Frank AO, Ziegler J, Klingenstein R, Schweimer K, Willbold D, Korth C, Rosch P, Schwarzinger S: Binding of TCA to the prion protein: mechanism, implication for therapy, and application as probe for complex formation of bio-macromolecules. J Biomol Struct Dyn. 2009 Oct;27(2):163-70.
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. |
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