학술논문
Identification of compounds inhibiting prion replication and toxicity by removing PrP C from the cell surface.
Document Type
Academic Journal
Author
Biggi S; Dulbecco Telethon Laboratory of Prions and Amyloids, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.; Pancher M; HTS Core Facility, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.; Stincardini C; Dulbecco Telethon Laboratory of Prions and Amyloids, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.; Luotti S; Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.; Massignan T; HTS Core Facility, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.; Dalle Vedove A; Laboratory of Protein Crystallography and Structure-Based Drug Design, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.; Astolfi A; Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy.; Gatto P; HTS Core Facility, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.; Lolli G; Laboratory of Protein Crystallography and Structure-Based Drug Design, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.; Barreca ML; Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy.; Bonetto V; Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.; Adami V; HTS Core Facility, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.; Biasini E; Dulbecco Telethon Laboratory of Prions and Amyloids, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.
Source
Publisher: Wiley on behalf of the International Society for Neurochemistry Country of Publication: England NLM ID: 2985190R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1471-4159 (Electronic) Linking ISSN: 00223042 NLM ISO Abbreviation: J Neurochem Subsets: MEDLINE
Subject
Language
English
Abstract
The vast majority of therapeutic approaches tested so far for prion diseases, transmissible neurodegenerative disorders of human and animals, tackled PrP Sc , the aggregated and infectious isoform of the cellular prion protein (PrP C ), with largely unsuccessful results. Conversely, targeting PrP C expression, stability or cell surface localization are poorly explored strategies. We recently characterized the mode of action of chlorpromazine, an anti-psychotic drug known to inhibit prion replication and toxicity by inducing the re-localization of PrP C from the plasma membrane. Unfortunately, chlorpromazine possesses pharmacokinetic properties unsuitable for chronic use in vivo, namely low specificity and high toxicity. Here, we employed HEK293 cells stably expressing EGFP-PrP to carry out a semi-automated high content screening (HCS) of a chemical library directed at identifying non-cytotoxic molecules capable of specifically relocalizing PrP C from the plasma membrane as well as inhibiting prion replication in N2a cell cultures. We identified four candidate hits inducing a significant reduction in cell surface PrP C , one of which also inhibited prion propagation and toxicity in cell cultures in a strain-independent fashion. This study defines a new screening method and novel anti-prion compounds supporting the notion that removing PrP C from the cell surface could represent a viable therapeutic strategy for prion diseases.
(© 2019 International Society for Neurochemistry.)
(© 2019 International Society for Neurochemistry.)