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 protein, called the cellular prion protein (abbreviated PrP), into an aberrant form, called the scrapie prion protein (abbreviated PrPSc). Once formed, PrPSc behaves like an infectious agent (prion), propagating by inducing the conversion of additional PrP molecules, accumulating in large aggregates in brain tissues, and ultimately damaging the nervous system. 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 improve its pharmacological properties and make it safely administrable to humans. The project intends to directly pursue these tasks, with the ultimate goal to define a novel pharmacological option to test in prion disease patients.