Maria Laura Bolognesi1, Salvatore Bongarzone2, Suzana Aulic3, Hoang Ngoc Ai Tran4, Federica Prati1, Paolo Carloni5, Giuseppe Legname3. 1. Department of Pharmacy & Biotechnology, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy. 2. Division of Imaging Sciences & Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, SE1 7EH, UK. 3. SISSA, Neuroscience Department, Via Bonomea 265, 34136 Trieste, Italy. 4. Department of Comparative Biology & Experimental Medicine, University of Calgary, Calgary, Canada. 5. Computational Biomedicine section (IAS-5), Institute of Advanced Simulation (IAS), 52425 Jülich, Germany.
Abstract
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.
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-hydroxyquinolinemetal 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.
Authors: N C Ferreira; L M Ascari; A G Hughson; G R Cavalheiro; C F Góes; P N Fernandes; J R Hollister; R A da Conceição; D S Silva; A M T Souza; M L C Barbosa; F A Lara; R A P Martins; B Caughey; Y Cordeiro Journal: Antimicrob Agents Chemother Date: 2018-01-25 Impact factor: 5.191