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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.

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