Cationic polysaccharides as antiprion agents.
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.
Yudovin-Farber
Ira
I
Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Azzam
Tony
T
Metzer
Esther
E
Taraboulos
Albert
A
Domb
Abraham J
AJ
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
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