Innovative Non-PrP-Targeted Drug Strategy Designed to Enhance Prion Clearance

[Image: see text] Prion diseases are a group of neurodegenerative disorders characterized by the accumulation of misfolded prion protein (called PrP(Sc)). Although conversion of the cellular prion protein (PrP(C)) to PrP(Sc) is still not completely understood, most of the therapies developed until now are based on blocking this process. Here, we propose a new drug strategy aimed at clearing prions without any direct interaction with neither PrP(C) nor PrP(Sc). Starting from the recent discovery of SERPINA3/SerpinA3n upregulation during prion diseases, we have identified a small molecule, named compound 5 (ARN1468), inhibiting the function of these serpins and effectively reducing prion load in chronically infected cells. Although the low bioavailability of this compound does not allow in vivo studies in prion-infected mice, our strategy emerges as a novel and effective approach to the treatment of prion disease.