Pharmacological Degraders for the Cellular Prion Protein

Prion diseases are rare neurodegenerative conditions affecting humans and other mammals. These pathologies can be transmitted via genetic or infectious routes and are responsible for the epidemics of bovine spongiform encephalopathy, also known as mad cow disease, which mainly affected Europe in the late 1990s. Prion diseases are caused by the conversion of a normal neuronal protein, called PrP, into an aberrant form, called PrP^Sc. Once formed, PrP^Sc behaves like an infectious agent (prion), propagating by inducing the conversion of additional PrP molecules, accumulating in large aggregates in neuronal tissues, and ultimately damaging the brain. While no cures are currently available for these disorders, recent evidence has provided strong support for the idea of lowering the expression of the normal form of PrP to treat prion diseases. We have recently developed a new technology, called PPI-FIT, for identifying drugs capable of selectively lowering the expression of target proteins. Thanks to PPI-FIT, we have identified a promising molecule able to reduce PrP levels and block prion replication in cells. However, the compound must be further developed to make it safely administrable to patients. The project intends to pursue this goal. The results of this research could provide a unique pharmacological resource for the treatment of prion diseases and much more frequent disorders of the nervous system, such as Alzheimer's and Parkinson's diseases, in which a harmful role of PrP has recently been identified.