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First published online 11 October 2005
doi: 10.1242/jcs.02609

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Charged bipolar suramin derivatives induce aggregation of the prion protein at the cell surface and inhibit PrP^Sc replication

¹ Prion Research Group, Institute of Virology, Technical University of Munich, Biedersteiner-Str. 29, 80802 Munich, Germany
² Pharmaceutical Institute, Rheinische Friedrich-Wilhelms-Universität Bonn, An der Immenburg 4, 53121 Bonn, Germany
³ Institute for Novel and Emerging Infectious Diseases, Friedrich Loeffler Institute, Boddenblick 5a, 17493 Greifswald-Insel Riems, Germany

^* Author for correspondence (e-mail: schaetzl{at}lrz.tum.de)

Accepted 20 July 2005

The conversion of the cellular prion protein (PrP^c) into a pathogenic isoform (PrP^Sc) 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 PrP^Sc accumulation in cell culture. Among these, the drug suramin induces aggregation and re-targeting of PrP^c to endocytic compartments. Plasma membrane and sites of conversion into PrP^Sc are thereby bypassed. 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 symmetrical aromatic sulfonic acid substitutions inhibited de novo synthesis of PrP^Sc and induced aggregation and reduction of the half-life of PrP^c without downregulating PrP^c cell surface expression. Half-molecule compounds lacking the symmetrical bipolar structure or the anionic groups had no effect on PrP^Sc synthesis or PrP^c solubility. Cell surface expression of PrP^c was necessary for the activity of effective compounds. Suramin derivatives did not induce aggregation of PrP^c 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 PrP^Sc. 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 an anti-prion effect that differs from those characterising other sulphated polyanions and is dependent on the presence of the symmetrical anionic structure of these molecules.

Key words: Prion, PrP^c, PrP^Sc, Suramin, Bipolar structure, Anti-prion compound

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