BACKGROUND: The main pathogenic event of prion disorders has been identified in the deposition of the disease-associated prion protein (PrP(Sc)), which is accompanied by metal dyshomeostasis. RESULTS: The multitarget-directed ligand 1, designed by combining a heteroaromatic prion recognition motif to an 8-hydroxyquinoline metal chelator, has been developed as a potential antiprion disease-modifying agent. Importantly, 1 was found to effectively clear PrP(Sc) from scrapie-infected cells, and, at the same time, inhibit metal-induced prion aggregation and reactive oxygen species generation. 1 was also characterized in terms of pharmacokinetic properties in a preliminary in vitro investigation. CONCLUSION: Compound 1 has emerged as a suitable lead candidate against prion diseases and as a good starting point for a further optimization process.
|Titolo:||Rational approach to an antiprion compound with a multiple mechanism of action|
|Autori:||Bolognesi ML; Bongarzone S; Aulic S; Ai Tran HN; Prati F; Carloni P; Legname G|
|Rivista:||FUTURE MEDICINAL CHEMISTRY|
|Data di pubblicazione:||2015|
|Digital Object Identifier (DOI):||10.4155/fmc.15.79|
|Appare nelle tipologie:||1.1 Journal article|