Elimination of prions by branched polyamines and implications for therapeutics.
We report that branched polyamines, including polyamidoamide dendimers, polypropyleneimine, and polyethyleneimine, are able to purge PrP(Sc), the protease-resistant isoform of the prion protein, from scrapie-infected neuroblastoma (ScN2a) cells in culture. The removal of PrP(Sc) by these compounds depends on both the concentration of branched polymer and the duration of exposure. Chronic exposure of ScN2a cells to low noncytotoxic concentrations of branched polyamines for 1 wk reduced PrP(Sc) to an undetectable level, a condition that persisted at least 3 wk after removal of the compound. Structure-activity analysis revealed that a high surface density of primary amino groups is required for polyamines to eliminate PrP(Sc) effectively from cells. The removal of PrP(Sc) by branched polyamines is attenuated by chloroquine in living cells, and exposure of scrapie-infected brain extracts with branched polyamines at acidic pH rendered the PrP(Sc) susceptible to protease in vitro, suggesting that endosomes or lysozomes may be the site of action. Our studies suggest that branched polyamines might be useful therapeutic agents for treatment of prion diseases and perhaps a variety of other degenerative disorders.
Supattapone
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S
Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143-0518, USA.
Nguyen
H O
HO
Cohen
F E
FE
Prusiner
S B
SB
Scott
M R
MR
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy; D011073:Polyamines / Q000627:therapeutic use*; D011328:Prions / Q000378:metabolism*; D012608:Scrapie / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D013997:Time Factors
D011073:Polyamines; D011328:Prions