Carlo Mustazza*, Marco Sbriccoli, Paola Minosi and Carla Raggi Pages 5446 - 5479 ( 34 )
Prion pathologies are fatal neurodegenerative diseases caused by the misfolding of the physiological Prion Protein (PrPC) into a β-structure-rich isoform called PrPSc. 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 PrPSc as a target, but the existence of different prion strains arising from alternative conformations of PrPSc, limited the efficacy of the ligands to a straindependent ability. That has shifted research to PrPC ligands, which either act as chaperones, by stabilizing the native conformation, or inhibit its interaction with PrPSc. 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.
Prions, transmissible spongiform encephalopathies, scrapie, amyloid, histological dyes, Structure- Activity Relationship (SAR).
National Centre for Control and Evaluation of Medicines, Italian National Institute of Health, Viale Regina Elena 299, 00161 Rome, Department of Neurosciences, Italian National Institute of Health, Viale Regina Elena 299, 00161 Rome, National Centre for Drug Research and Evaluation, Italian National Institute of Health, Viale Regina Elena 299, 00161 Rome, National Centre for Control and Evaluation of Medicines, Italian National Institute of Health, Viale Regina Elena 299, 00161 Rome