Identification of novel fluorescent probes preventing PrP Sc replication in prion diseases
Autor: | Stefania Butini, Giuseppe Campiani, Giulia Chemi, Ludovica Zaccagnini, Sandra Gemma, Giuseppe Legname, Simone Brogi, Margherita Brindisi |
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Přispěvatelé: | Zaccagnini, Ludovica, Brogi, Simone, Brindisi, Margherita, Gemma, Sandra, Chemi, Giulia, Legname, Giuseppe, Campiani, Giuseppe, Butini, Stefania |
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Gene isoform PrPSc Proteins Cell Survival Protein Conformation 3D-QSAR Anti-Prion agents Pharmacophore modeling Prion Theranostic tools animal diseases Anti-Prion agent Quantitative Structure-Activity Relationship Context (language use) Protein aggregation 01 natural sciences Cell Line Prion Diseases Protein Aggregates 03 medical and health sciences Protein structure Drug Discovery Humans IC50 Fluorescent Dyes Pharmacology Virtual screening Tumor Cell Line Tumor Molecular Docking Simulation Drug Discovery3003 Pharmaceutical Science Organic Chemistry Chemistry General Medicine Virology nervous system diseases 0104 chemical sciences Cell biology 010404 medicinal & biomolecular chemistry 030104 developmental biology Pharmacophore |
Zdroj: | European Journal of Medicinal Chemistry. 127:859-873 |
ISSN: | 0223-5234 |
Popis: | 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. |
Databáze: | OpenAIRE |
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