Novel heparan mimetics potently inhibit the scrapie prion protein and its endocytosis.
During prion diseases the normal prion protein PrP(C) is refolded into an abnormal conformer PrP(Sc). We have studied the PrP(Sc) inhibiting activity of a library of synthetic heparan mimetic (HM) biopolymers. HMs are chemically derived dextrans obtained by successive substitutions with carboxymethyl, benzylamide, and sulfate groups on glucose residues. Some HMs eliminated PrP(Sc) from prion-infected cells after a 5 day course at 100 ng/ml and were 15 x potent than pentosan sulfate in this system. The anti-PrP(Sc) activity of HMs correlated with the degree of sulfation but was increased by benzylamidation. HMs did not reduce the synthesis of PrP(C) nor its attachment to lipid rafts, but instead blocked its conversion into PrP(Sc). The anti-PrP(Sc) HMs also prevented the uptake of prion rods by cultured cells. HMs may thus block the interaction of PrP(Sc) with a putative cellular receptor, possibly heparan sulfate. HMs provide an attractive chemical approach for the synthesis of TSE therapeutic and prophylactic reagents.
Schonberger
Oshrat
O
Department of Molecular Biology, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Horonchik
Lior
L
Gabizon
Ruth
R
Papy-Garcia
Dulce
D
Barritault
Denis
D
Taraboulos
Albert
A
D000818:Animals; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D032701:Biomimetics / Q000379:methods; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects*; D006497:Heparan Sulfate / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D019151:Peptide Library; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000187:drug effects; D014407:Tumor Cells, Cultured
D006497:Heparan Sulfate; D019151:Peptide Library; D018620:PrPSc Proteins