Discovery of Novel Anti-prion Compounds Using In Silico and In Vitro Approaches

Prion diseases are associated with the conformational conversion of the physiological form of cellular prion protein (PrP^C) to the pathogenic form, PrP^Sc. Compounds that inhibit this process by blocking conversion to the PrP^Sc could provide useful anti-prion therapies. However, no suitable drugs have been identified to date. To identify novel anti-prion compounds, we developed a combined structure- and ligand-based virtual screening system in silico. Virtual screening of a 700,000-compound database, followed by cluster analysis, identified 37 compounds with strong interactions with essential hotspot PrP residues identified in a previous study of PrP^C interaction with a known anti-prion compound (GN8). These compounds were tested in vitro using a multimer detection system, cell-based assays, and surface plasmon resonance. Some compounds effectively reduced PrP^Sc levels and one of these compounds also showed a high binding affinity for PrP^C. These results provide a promising starting point for the development of anti-prion compounds.