The transmissible spongiform encephalopathies (TSEs or prion diseases)are fatal untreatable neurodegenerative diseases such as scrapie, Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy and chronic wasting disease (CWD). TSE pathogenesis involves the accumulation of an abnormal protein, called PrPres, in infected hosts. We have previously identified sulfated glycans and phosphorothioate oligonucleotides as potent anti-prion compounds that are effective in inhibiting PrPres accumulation and slowing or prevent the progression of scrapie in experimental animals. This fiscal year, we have extended our studies of the binding of these types of inhibitors to recombinant prion protein using nuclear magnetic resonance, circular dichroism, fluorescence polarization and infrared spectroscopy. Pentosan polysulfate was found to stabilize a structure in the octapeptide repeat region of PrP.