Charged bipolar suramin derivatives induce aggregation of the prion protein at the cell surface and inhibit PrPSc replication.
The conversion of the cellular prion protein (PrPc) 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 PrPc 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 PrPc without downregulating PrPc cell surface expression. Half-molecule compounds lacking the symmetrical bipolar structure or the anionic groups had no effect on PrP(Sc) 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 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.
Nunziante
Max
M
Prion Research Group, Institute of Virology, Technical University of Munich, Biedersteiner-Str. 29, 80802 Munich, Germany.
Kehler
Claudia
C
Maas
Elke
E
Kassack
Matthias U
MU
Groschup
Martin
M
Schätzl
Hermann M
HM
D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism*; D003902:Detergents; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D006207:Half-Life; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D000071228:Polyelectrolytes; D011108:Polymers / Q000494:pharmacology; D018621:PrPC Proteins / Q000096:biosynthesis / Q000378:metabolism; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism; D012995:Solubility; D013498:Suramin / Q000031:analogs & derivatives* / Q000494:pharmacology*
D003902:Detergents; D000071228:Polyelectrolytes; D011108:Polymers; D018621:PrPC Proteins; D018620:PrPSc Proteins; D013498:Suramin