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 100ng/ml and were 15× 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.