Novel heparan mimetics potently inhibit the scrapie prion protein and its endocytosis

Biochem Biophys Res Commun. 2003 Dec 12;312(2):473-9. doi: 10.1016/j.bbrc.2003.10.150.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomimetic Materials / chemical synthesis
  • Biomimetic Materials / chemistry*
  • Biomimetic Materials / pharmacology*
  • Biomimetics / methods
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Endocytosis / drug effects*
  • Heparitin Sulfate / chemistry*
  • Heparitin Sulfate / pharmacology*
  • Mice
  • Neuroblastoma / metabolism*
  • Neuroblastoma / pathology
  • Peptide Library
  • PrPSc Proteins / antagonists & inhibitors*
  • PrPSc Proteins / chemistry*
  • PrPSc Proteins / drug effects
  • Tumor Cells, Cultured

Substances

  • Peptide Library
  • PrPSc Proteins
  • Heparitin Sulfate