NR AOXN
AU Nunziante,M.; Maas,E.; Schätzl,H.M.
TI Suramin derivatives inhibit PrPsc formation in prion-infected cells
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Poster session - IV-13
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-routing of PrPc to endocytic compartments, by-passing plasma membrane and sites of conversion into PrPsc. We compared these effects with those exerted by four Suramin derivatives in solubility and metabolic labelling assays. Treatment of infected neuroblastoma cells with derivatives NF023 and NF449, presenting symmetric aromatic structure, inhibited de-novo synthesis of PrPsc and induced aggregation of PrPc, without down-regulating PrPc cell surface expression, as seen in surface FACS analysis. Treatment with NF007 and ANTS, both lacking half of the aromatic rings, showed no effect on PrPsc synthesis or PrPc solubility. Suramin derivatives did not induce aggregation of PrPc retained in the ER using Brefeldin A, nor did they alter solubility of a PrP mutant transported directly from the TGN to endosomes/lysosomes. Our data reveal a novel mechanism of anti-prion effect differing from that seen for Suramin, as conversion was not inhibited by re-routing. Effects exerted by Suramin derivatives seem to take place at a post-TGN site, possibly close to the compartment of conversion into PrPsc, and to be dependent on the presence of the symmetric structure of these molecules.
AD Max Nunziante, Elke Maas, Hermann M. Schätzl, Technical University of Munich, Institute of Virology, Germany
SP englisch
PO Deutschland