Antiprion compounds that reduce PrP(Sc) levels in dividing and stationary-phase cells

During prion diseases, a normally benign, host protein, denoted PrP(C), undergoes alternative folding into the aberrant isoform, PrP(Sc). We used ELISA to identify and confirm hits in order to develop leads that reduce PrP(Sc) in prion-infected dividing and stationary-phase mouse neuroblastoma (ScN2a-cl3) cells. We tested 52,830 diverse small molecules in dividing cells and 49,430 in stationary-phase cells. This led to 3100 HTS and 970 single point confirmed (SPC) hits in dividing cells, 331 HTS and 55 confirmed SPC hits in stationary-phase cells as well as 36 confirmed SPC hits active in both. Fourteen chemical leads were identified from confirmed SPC hits in dividing cells and three in stationary-phase cells. From more than 682 compounds tested in concentration-effect relationships in dividing cells to determine potency (EC50), 102 had EC50 values between 1 and 10 μM and 50 had EC50 values of