Background: The main pathogenic event of prion disorders has been identified in the deposition of the disease-associated prion protein (PrPSc), 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 PrPSc 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
Bolognesi, M.L., Bongarzone, S., Aulic, S., Ai Tran, H.N., Prati, F., Carloni, P., et al. (2015). Rational approach to an antiprion compound with a multiple mechanism of action. FUTURE MEDICINAL CHEMISTRY, 7(16), 2113-2120 [10.4155/fmc.15.79].
Rational approach to an antiprion compound with a multiple mechanism of action
BOLOGNESI, MARIA LAURA;BONGARZONE, SALVATORE;PRATI, FEDERICA;
2015
Abstract
Background: The main pathogenic event of prion disorders has been identified in the deposition of the disease-associated prion protein (PrPSc), 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 PrPSc 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 processI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
