Small Molecules with Anti-Prion Activity

Abstract

Prion pathologies are fatal neurodegenerative diseases caused by the misfolding of the physiological Prion Protein (PrP^C) into a β-structure-rich isoform called PrP^Sc. To date, there is no available cure for prion diseases and just a few clinical trials have been carried out. The initial approach in the search of anti-prion agents had PrP^Sc as a target, but the existence of different prion strains arising from alternative conformations of PrP^Sc, limited the efficacy of the ligands to a straindependent ability. That has shifted research to PrP^C ligands, which either act as chaperones, by stabilizing the native conformation, or inhibit its interaction with PrP^Sc. The role of transition-metal mediated oxidation processes in prion misfolding has also been investigated. Another promising approach is the indirect action via other cellular targets, like membrane domains or the Protein- Folding Activity of Ribosomes (PFAR). Also, new prion-specific high throughput screening techniques have been developed. However, so far no substance has been found to be able to extend satisfactorily survival time in animal models of prion diseases. This review describes the main features of the Structure-Activity Relationship (SAR) of the various chemical classes of anti-prion agents.