NR ATIH
AU Nunziante,M.; Kehler,C.; Maas,E.; Kassack,M.U.; Groschup,M.H.; Schätzl,H.M.
TI Charged bipolar suramin derivatives induce aggregation of the prion protein at the cell surface and inhibit PrPsc replication
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Poster Session: Cell Biology of PrPc and PrPsc CELL-39
PT Konferenz-Poster
AB The conversion of the cellular prion protein (PrPc) into a pathogenic isoform (PrPsc) is one of the underlying events in the pathogenesis of the fatal transmissible spongiform encephalopathies (TSEs). Numerous compounds have been described to inhibit prion replication and PrPsc accumulation in cell culture. Among these, the drug suramin induces aggregation and re-targeting of PrPc to endocytic compartments. Plasma membrane and sites of conversion into PrPsc are thereby by-passed. In the present study, a library of suramin analogues was tested as a potential class of new anti-prion compounds and the molecular mechanisms underlying these effects were analysed. Treatment of prion-infected neuroblastoma cells with compounds containing symmetric aromatic sulfonic acid substitutions inhibited de novo synthesis of PrPsc and induced aggregation and reduction of the half-life of PrPc without down-regulating PrPc cell surface expression. Half-molecule compounds lacking the symmetric bipolar structure or the anionic groups had no effect on PrPsc synthesis or PrPc solubility. Cell surface expression of PrPc was necessary for the activity of effective compounds. Suramin derivatives did not induce aggregation of PrPc when transport along the secretory pathway was compromised, suggesting that their effects occur at a post-Trans Golgi Network (TGN) site, possibly close to the compartment of conversion into PrPsc. In vitro studies with recombinant PrP demonstrated that the inhibitory effect correlated with direct binding to PrP and induction of insoluble PrP aggregates. Our data reveal a mechanism of anti-prion effect which differs from the ones characterising other sulphated polyanions and dependent on the presence of the symmetric anionic structure of these molecules.
AD M.Nunziante, C.Kehler, E.Maas, H.M.Schätzl, Prion Research Group, Institute of Virology, Technical University of Munich; M.U.Kassack, Pharmaceutical Institute, Rheinische Friedrich-Wilhelms-Universität Bonn, An der Immenburg 4, D-53121 Bonn, Germany; M.Groschup, Institute for Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institute, Greifswald - Insel Riems, Germany
SP englisch
PO Deutschland