In silico/in vitro screening and hit evaluation identified new phenothiazine anti-prion derivatives
| Autor: | Annachiara Gandini, Maria Laura Bolognesi, Giulia Rossetti, Arianna Colini Baldeschi, Paolo Carloni, Ludovica Zaccagnini, Thanh Hoa Tran, Giuseppe Legname, Giulia Salzano |
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| Přispěvatelé: | Zaccagnini L., Rossetti G., Tran T.H., Salzano G., Gandini A., Colini Baldeschi A., Bolognesi M.L., Carloni P., Legname G. |
| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Gene isoform animal diseases In silico Drug Evaluation Preclinical Quantitative Structure-Activity Relationship Phenothiazine Prion Protein Anti-prion agent 01 natural sciences Prion Proteins Cell Line Mice 03 medical and health sciences Phenothiazines Settore BIO/10 - Biochimica Drug Discovery medicine Animals ddc:610 030304 developmental biology Pharmacology 0303 health sciences Molecular Structure Animal 010405 organic chemistry Chemistry Organic Chemistry Neurotoxicity RT-QuIC Competition assay QSAR-model General Medicine medicine.disease In vitro nervous system diseases 0104 chemical sciences Blot Mechanism of action Biochemistry Cell culture Prion medicine.symptom Pharmacophore Chronic treatment |
| Zdroj: | European journal of medicinal chemistry 196, 112295 (2020). doi:10.1016/j.ejmech.2020.112295 |
| ISSN: | 0223-5234 |
| Popis: | Prion diseases or transmissible spongiform encephalopathies (TSEs) are a group of rare neurodegenerative disorders. TSEs are characterized by the accumulation of prions (PrPSc) that represent pathological isoforms of the physiological cellular prion protein PrPC. Although the conversion of PrPC to PrPSc is still not completely understood, blocking this process may lead to develop new therapies. Here, we have generated a pharmacophore model, based on anti-prion molecules reported in literature to be effective in phenotypic assay. The model was used to conduct a virtual screen of commercial compound databases that selected a small library of ten compounds. These molecules were then screened in mouse neuroblastoma cell line chronically infected with prions (ScN2a) after excluding neurotoxicity. 1 has been identified as the therapeutic hit on the basis of the following evidence: chronic treatments of ScN2a cells using 1 eliminate PrPSc loaded in both Western blotting analysis and Real-Time Quaking-Induced Conversion (RT-QuIC) assay. We also proposed the mechanism of action of 1 by which it has the ability to bind PrPC and consequentially blocks prion conversion. Herein we describe the results of these efforts. |
| Databáze: | OpenAIRE |
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