Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12779/6726
Title: Identification of novel fluorescent probes preventing PrP(Sc) replication in prion diseases
Authors: Zaccagnini, Ludovica
Brogi, Simone
Brindisi, Margherita 
Gemma, Sandra 
Chemi, Giulia 
Legname, Giuseppe
Campiani, Giuseppe 
Butini, Stefania 
Keywords: 3D-QSAR; Anti-Prion agents; Pharmacophore modeling; Prion; Theranostic tools
Issue Date: 2016
Project: None 
Journal: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Abstract: 
Prion diseases are serious, not curable neurodegenerative disorders caused by the accumulation of the misfolded protein PrP(Sc) that represents the pathological variant of the normally folded cellular protein PrP(C). Molecules that bind the cellular isoform PrP(C) preventing its misfolding, could arrest the progression of pathological conditions related to the abnormal PrP protein. In this context, by combining 3D-QSAR model, derived from pharmacophore-based alignment, with molecular docking procedures and physico-chemical properties prediction we have developed a virtual screening protocol to find novel chemicals able to prevent PrP(C) misfolding. We identified different hits characterized by low toxicity and able to inhibit PrP(Sc) accumulation in vitro in prion-infected neuroblastoma cell lines (ScN2a). In this assay, the pyrroloquinoxaline hydrazone 96 showed the higest potency with an IC50 value of 1.6 μM. Pyrroloquinoxaline 96 was demonstrated also to bind PrP(Sc) aggregates in infected ScN2a cells with a fluorescence pattern comparable to that found for Thioflavin-T. In consideration of its satisfactory physico-chemical properties, including predicted blood brain barrier permeability, 96 could represent an interesting prototypic hit for the development of diagnostic and therapeutic probes for prion diseases.
Description: 
98303
URI: http://hdl.handle.net/20.500.12779/6726
ISSN: 0223-5234
DOI: 10.1016/j.ejmech.2016.10.064
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