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
Aulic, Suzana;
2015-01-01
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 process.File | Dimensione | Formato | |
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10.4105:fmc.15.79.pdf
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