NR AREW
AU Wolff,M.; Hänel,K.; Santuccione,A.; Schachner,M.; Willbold,D.; Riesner,D.
TI Therapy of Transmissible Spongiform Encephalopathies with PrP-binding Peptides selected by Phage Display
QU TSE-Forum, 4. Kongress - Nationale TSE-Forschungsplattform, Düsseldorf 28.10.-29.10.2004, Poster THE-06
PT Konferenz-Poster
AB
The major component of the infectious agent of Transmissible Spongiform Encephalopathies i.e. prions is the host encoded Prion-Protein (PrP). In contrast to the cellular predominantly alpha-helical isoform, the disease associated PrP is mainly ß-structured and forms large insoluble aggregates. Conversion of PrP from the alpha-helical conformation into the ß-structured isoform is a central event in the course of TSEs. Since ß-structured PrP is essential for infectivity it is presumably the exclusive cause of the disease. Therefore stabilization of the cellular isoform and inhibition of the conversion to the ß-structured state may be a suitable approach for prevention or therapy of prion diseases. This stabilization can be achieved by PrP ligands binding specifically the cellular isoform.
We identified more than hundred PrP-binding peptide sequences by phage display. From these 40 peptides were synthesized. Afterwards we examined their ability to inhibit conversion of PrP into the ß-structured isoform in a SDS-based in vitro conversion system. Their influences onto changes in secondary structure were determined by circular dichroism spectroscopy. The potential to inhibit formation of aggregates was analyzed by differential ultracentrifugation. Finally we could identify one peptide that enhances PrP solubility at low SDS concentrations and is able to delay conversion into the ß-structured isoform. Thus stabilization of the cellular isoform of PrP by specifically binding peptides is possible. This points out a promising way for therapy of prion diseases.
AD Michael Wolff, Karen Hänel, Dieter Willbold, Detlev Riesner, Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, D-40225; Karen Hänel, Dieter Willbold, Institut für Biologische Informationsverarbeitung, Forschungszentrum Jülich, D-52425; Antonella Santuccione, Melitta Schachner, Zentrum für Molekulare Neurobiologie, Universität Hamburg, D-29246
SP englisch
PO Deutschland
OR Tagungsband