Prion diseases are devastating neurodegenerative disorders with no known cure. This application proposes to address critical knowledge gaps in the discovery of anti-prion drugs and the identification of their pharmacological targets. We will focus on one particular class of compounds, exemplified by a molecule designated LD-7, which emerged from an unconventional, high-throughput screen we carried out based on the cellular toxicity of a mutant form of PrP. LD-7 is a potent inhibitor of PrPSc accumulation in scrapie-infected neuroblastoma cells in culture. We have defined the pharmacophore of LD-7 and created a more potent derivative, JZ-107. Our objective here is to identify the molecular targets of the LD-7/JZ-107 class of PrPSc inhibitors.
In aim #1, we will pursue exciting preliminary data indicating that these inhibitors are ligands for several well-known CNS receptors. To determine whether any of these receptors are biologically relevant targets, we will test whether altering their activity pharmacologically or manipulating their expression levels genetically influences PrPSc levels in scrapie-infected neuroblastoma cells.
In Aim #2, we will take advantage of a of a unique affinity probe we have developed to identify molecular targets for the inhibitors via chemical tagging and mass spectrometry. The use of a novel cellular screening assay has allowed us to identify a new class of anti-prion compounds that may have escaped detection in previous screening efforts. These compounds represent particularly valuable therapeutic leads for treatment of prion diseases, given their chemical similarity to ligands for several well-known CNS receptors. Identifying the molecular targets for these compounds will provide new insights into the mechanisms of PrPSc formation and how PrPSc produces neurotoxic effects.
Prion diseases are fatal neurodegenerative disorders of humans and animals that pose a grave threat to public health, and endanger the safety of the food, blood and organ supplies. There are currently no cures for prion diseases. This grant application aims to study a novel class of drug molecules that reduces prion levels in a model system. These molecules represent promising therapeutic leads, and will serve as tools to understand the cellular processes underlying prion diseases.
