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
Rational approach to an antiprion compound with a multiple mechanism of action / Bolognesi, Maria Laura; Bongarzone, Salvatore; Aulic, Suzana; Ai Tran, Hoang Ngoc; Prati, Federica; Carloni, Paolo; Legname, Giuseppe. - In: FUTURE MEDICINAL CHEMISTRY. - ISSN 1756-8919. - STAMPA. - 7:16(2015), pp. 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.