Rational approach to an antiprion compound with a multiple mechanism of action.
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.


CONCLUSIONS
Compound 1 has emerged as a suitable lead candidate against prion diseases and as a good starting point for a further optimization process.
Department of Pharmacy & Biotechnology, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
Maria Laura
ML
Bolognesi
Division of Imaging Sciences & Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, SE1 7EH, UK.
Salvatore
S
Bongarzone
SISSA, Neuroscience Department, Via Bonomea 265, 34136 Trieste, Italy.
Suzana
S
Aulic
Department of Comparative Biology & Experimental Medicine, University of Calgary, Calgary, Canada.
Hoang Ngoc
HN
Ai Tran
Department of Pharmacy & Biotechnology, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
Federica
F
Prati
Computational Biomedicine section (IAS-5), Institute of Advanced Simulation (IAS), 52425 Jülich, Germany.
Paolo
P
Carloni
SISSA, Neuroscience Department, Via Bonomea 265, 34136 Trieste, Italy.
Giuseppe
G
Legname
D015195:Drug Design; D006801:Humans; D008024:Ligands; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015125:Oxyquinoline / Q000737:chemistry / Q000494:pharmacology*; D017096:Prion Diseases / Q000188:drug therapy* / Q000378:metabolism; D011328:Prions / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
D008024:Ligands; D009942:Organometallic Compounds; D011328:Prions; D017382:Reactive Oxygen Species; D015125:Oxyquinoline