NR AOUV
AU Klingenstein,R.; von Coburg,A.; Schwarzmann,G.; Korth,C.
TI Search for molecular targets of heterocyclic antiprion compounds
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Poster session - IV-08
PT Konferenz-Poster
AB
Prion diseases are transmissible neurodegenerative diseases of humans and animals that are invariably fatal since no treatment exists. Paramount to the disease process is the accumulation of the disease-causing prion protein PrPsc, a misfolded pathogenic isoform of the normal cellular prion protein, PrPc. Heterocyclic compounds like phenothiazine and acridine derivatives have been demonstrated to exhibit antiprion potency in a cell culture model of prion disease.
Elucidating the mechanism of action of the heterocyclic antiprion compounds will lead to more potent compounds optimized for their antiprion effects and to new targets in the pharmacotherapy of neurodegenerative diseases. We have synthesized second generation heterocyclic antiprion compounds (2G-HAC), derivatives of bis-acridines that display a ca. tenfold higher antiprion activity than quinacrine, and developed a protocol to identify its receptors. Like quinacrine, the 2G-HAC localize mainly to lysosomes underlining the importance of this cell compartment for maintaining prion infection an thus providing a source for potential interacting molecules. 2G-HAC are crosslinked to interacting molecules from lysosomes with a photoactivatable bifunctional crosslinker and identified by fluorimetry. We have also raised antibodies against the heterocyclic scaffold and its aliphatic side chain, chemical constituents mandatory for the antiprion effect. With these methods receptor molecules for the heterocyclic antiprion compounds can be identified and candidate interacting molecules will be discussed.
Supported by the Bundesministerium für Bildung und Forschung, Germany.
AD Ralf Klingenstein, Carsten Korth, Heinrich Heine University Düsseldorf, Institute for Neuropathology, Germany; Alexander von Coburg, Günther Schwarzmann, University of Bonn, Kekule Institute for Organic Chemistry and Biochemistry
SP englisch
PO Deutschland