During prion diseases the normal prion protein PrPC is refolded into an abnormal conformer PrPSc. We have studied the PrPSc 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 PrPSc from prion-infected cells after a 5 day course at 100ng/ml and were 15x potent than pentosan sulfate in this system. The anti-PrPSc activity of HMs correlated with the degree of sulfation but was increased by benzylamidation. HMs did not reduce the synthesis of PrPC nor its attachment to lipid rafts, but instead blocked its conversion into PrPSc. The anti-PrPSc HMs also prevented the uptake of prion rods by cultured cells. HMs may thus block the interaction of PrPSc with a putative cellular receptor, possibly heparan sulfate. HMs provide an attractive chemical approach for the synthesis of TSE therapeutic and prophylactic reagents. (C) 2003 Elsevier Inc. All rights reserved.