Discovery of 2-Aminothiazoles as Potent Antiprion Compounds

Prion diseases are fatal, untreatable neurodegenerative diseases caused by the accumulation of the mis-folded, infectious isoform of the prion protein (PrP), termed PrPSc. In an effort to identify novel inhibitors of prion formation, we utilized a high-throughput enzyme-linked immunosorbent assay (ELISA) to evaluate PrPSc reduction in prion-infected neuroblastoma cell lines (ScN2a). We screened a library of similar to 10,000 diverse small molecules in 96-well format and identified 121 compounds that reduced PrPSc levels at a concentration of 5 mu M. Four chemical scaffolds were identified as potential candidates for chemical optimization based on the presence of preliminary structure-activity relationships (SAR) derived from the primary screening data. A follow-up analysis of a group of commercially available 2-aminothiazoles showed this class as generally active in ScN2a cells. Our results establish 2-aminothiazoles as promising candidates for efficacy studies of animals and validate our drug discovery platform as a viable strategy for the identification of novel lead compounds with antiprion properties.