Unfolding prion misfolding and the challenge of identifying effective therapeutics: is there hope on the horizon?

Prion diseases are rare, fatal neurodegenerative disorders caused by the conformational conversion of cellular prion protein (PrP) into a pathogenic counterpart called PrP^Sc, that replicates by templated misfolding. The resulting misfolding cascade leads to synaptic failure and neuronal loss. Despite major advances in understanding prion structure and biology, no therapies exist. The mechanism of prion propagation challenges conventional drug discovery, limiting targets. Small molecules, immunotherapies, and gene silencing, have shown limited clinical success. Increasingly, research is shifting toward alternative strategies to modulate proteostasis, enhance clearance, or target transient folding and misfolding intermediates of PrP, offering new therapeutic opportunities. However, these emerging strategies remain at an early conceptual or preclinical stage, and significant translational hurdles remain.

This chapter reviews prion drug discovery through the lens of PrP energy landscape. It summarizes efforts to target PrP conversion and highlights emerging approaches focused on degradation and intermediate targeting. Advances in structural biology and computational modelling are discussed as tools to identify novel therapeutic vulnerabilities.

The persistent failure of conventional strategies underscores the need for innovative approaches. Targeting transient conformational intermediates and exploiting cellular quality-control systems may redefine druggability in prion diseases and open new avenues for effective intervention.