Journal Article

PreJuSER-6512

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Binding of TCA to the prion protein: mechanism, implication for therapy, and application as probe for complex formation of bio-macromolecules

Mangels, C. ; Frank, A. O. ; Ziegler, J. ; Klingenstein, R. ; Schweimer, K. ; Willbold, D.FZJ* ; Korth, C. ; Rösch, P. ; Schwarzinger, S.

2009
Adenine Press Guilderland, NY

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Abstract: Tricyclic aromatic compounds (TCA) are promising candidates for treatment of transmissible spongiform encephalopathies. Direct binding to the cellular prion protein (PrPC) 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 PrPC. Because biologically inactive 9-aminoacridine (9-aa) binds with similar K-D as anti-prion active quinacrine, direct interaction with PrPC 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.

Keyword(s): J ; Conformational disease (auto) ; Prion protein (auto) ; Quinacrine (auto) ; 9-aminoacridine (auto) ; Drug design (auto) ; Ligand binding (auto) ; NMR-spectroscopy (auto) ; in vitro binding assay (auto) ; Relaxation (auto)

Note: We thank Dr. Vilma Martins for providing a plasmid with the human PRNP-gene. Financial support from the Bavarian Prion Research Platform (ForPrion) and the Volkswagen-Stiftung (1/79968) is gratefully acknowledged.

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Contributing Institute(s):

1. Strukturbiochemie (ISB-3)
2. Jülich Aachen Research Alliance - High-Performance Computing (JARA-HPC)

Research Program(s):

1. Funktion und Dysfunktion des Nervensystems (P33)

Appears in the scientific report 2009

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