title: Identification of novel fluorescent probes preventing PrPScreplication in prion diseases.
abstract: Prion diseases are serious, not curable neurodegenerative disorders caused by the accumulation of the misfolded protein PrPScthat represents the pathological variant of the normally folded cellular protein PrPC. Molecules that bind the cellular isoform PrPCpreventing 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 PrPCmisfolding. We identified different hits characterized by low toxicity and able to inhibit PrPScaccumulation in vitro in prion-infected neuroblastoma cell lines (ScN2a). In this assay, the pyrroloquinoxaline hydrazone 96 showed the higest potency with an IC50value of 1.6 μM. Pyrroloquinoxaline 96 was demonstrated also to bind PrPScaggregates 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.
authors.affiliation: Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), via Bonomea 265, 34136 Trieste, Italy.
authors.forename: Ludovica
authors.initials: L
authors.lastname: Zaccagnini
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy; Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Brogi
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy; Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Brindisi
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy; Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy. Electronic address: gemma@unisi.it.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy; Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Chemi
authors.affiliation: Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), via Bonomea 265, 34136 Trieste, Italy. Electronic address: legname@sissa.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Legname
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy; Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy; Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005456:Fluorescent Dyes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D018620:PrPSc Proteins / Q000737:chemistry* / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism*; D066329:Protein Aggregates / Q000187:drug effects*; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship
chemical_list: D005456:Fluorescent Dyes; D018620:PrPSc Proteins; D066329:Protein Aggregates
keywords: 3D-QSAR; Anti-Prion agents; Pharmacophore modeling; Prion; Theranostic tools