title: Cationic polysaccharides as antiprion agents.
abstract: Cationic polysaccharides were synthesized by conjugation of various oligoamines to oxidized polysaccharides by reductive amination and tested for antiprion activity. Polycations of dextran, pullulan and arabinogalactan grafted with oligoamines of 2 to 4 amino groups were investigated for their ability to eliminate PrP(Sc), the protease-resistant isoform of the prion protein, from chronically infected neuroblastoma cells, ScN2a-M. The proteinase K (PK)-resistant PrP elimination depends on both the concentration of the reagent and the duration of exposure. The most potent compound was found to be dextran-spermine that caused depletion of PrP(Sc) to undetectable levels at concentration of 31 ng/mL after 4 days of exposure. Activity analysis revealed that grafted oligoamine indentity of the polycation plays a significant role in elimination of PK-resistant PrP from chronically infected N2a-M cells, regardless of the polysaccharide used. Dextran-spermine conjugates were modified with oleic acid and with methoxypoly(ethylene glycol) (MPEG) at various degrees of substitution for further studies and their antiprion activity was examined. Substitution of dextran-spermine with MPEG or oleic acid slightly decreases its activity as a function of MPEG/oleic acid content. These findings confirm previous reports that polycations are effective in eliminating PrP(Sc) in vitro.
authors.affiliation: Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Ira
authors.initials: I
authors.lastname: Yudovin-Farber
authors.forename: Tony
authors.initials: T
authors.lastname: Azzam
authors.forename: Esther
authors.initials: E
authors.lastname: Metzer
authors.forename: Albert
authors.initials: A
authors.lastname: Taraboulos
authors.forename: Abraham J
authors.initials: AJ
authors.lastname: Domb
mesh_terms: D000818:Animals; D002412:Cations; D045744:Cell Line, Tumor; D003911:Dextrans / Q000737:chemistry; D019286:Endopeptidase K / Q000378:metabolism; D005685:Galactans / Q000737:chemistry; D005936:Glucans / Q000737:chemistry; D051379:Mice; D010426:Pentosan Sulfuric Polyester / Q000737:chemistry / Q000494:pharmacology; D011073:Polyamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011134:Polysaccharides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D002412:Cations; D003911:Dextrans; D005685:Galactans; D005936:Glucans; D011073:Polyamines; D011134:Polysaccharides; D018620:PrPSc Proteins; D010426:Pentosan Sulfuric Polyester; C009109:pullulan; D019286:Endopeptidase K; C005653:arabinogalactan