Pyridobenzothiazolones Exert Potent Anti-Dengue Activity by Hampering Multiple Functions of NS5 Polymerase
| Autor: | Cannalire, Rolando, Chan, Kitti Wing Ki, Burali, Maria Sole, Gwee, Chin Piaw, Wang, Sai, Astolfi, Andrea, Massari, Serena, Sabatini, Stefano, Tabarrini, Oriana, Mastrangelo, Eloise, Barreca, Maria Letizia, Cecchetti, Violetta, Vasudevan, Subhash G., Manfroni, Giuseppe |
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| Přispěvatelé: | Cannalire, Rolando, Wing Ki Chan, Kitti, Sole Burali, Maria, Piaw Gwee, Chin, Wang, Sai, Astolfi, Andrea, Massari, Serena, Sabatini, Stefano, Tabarrini, Oriana, Mastrangelo, Eloise, Letizia Barreca, Maria, Cecchetti, Violetta, G Vasudevan, Subhash, Manfroni, Giuseppe |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Untranslated region
viruses Zika inhibitors PROTEIN Dengue virus medicine.disease_cause Biochemistry chemistry.chemical_compound RNA polymerase Drug Discovery medicine Flavivirus Infections Polymerase NS3 biology Dengue inhibitors Organic Chemistry RNA virus diseases Ligand (biochemistry) Antivirals Virology NS5 RdRp inhibitors protein-protein interaction inhibitors chemistry REPLICATION biology.protein |
| Zdroj: | ACS Med Chem Lett ACS medicinal chemistry letters 11 (2020): 773–782. doi:10.1021/acsmedchemlett.9b00619 info:cnr-pdr/source/autori:Cannalire, Rolando and Chan, Kitti Wing Ki and Burali, Maria Sole and Gwee, Chin Piaw and Wang, Sai and Astolfi, Andrea and Massari, Serena and Sabatini, Stefano and Tabarrini, Oriana and Mastrangelo, Eloise and Barreca, Maria Letizia and Cecchetti, Violetta and Vasudevan, Subhash G. and Manfroni, Giuseppe/titolo:Pyridobenzothiazolones Exert Potent Anti-Dengue Activity by Hampering Multiple Functions of NS5 Polymerase/doi:10.1021%2Facsmedchemlett.9b00619/rivista:ACS medicinal chemistry letters/anno:2020/pagina_da:773/pagina_a:782/intervallo_pagine:773–782/volume:11 |
| Popis: | [Image: see text] Treatment of dengue virus (DENV) and other flavivirus infections is an unmet medical need. The highly conserved flaviviral NS5 RNA-dependent RNA polymerase (RdRp) is an attractive antiviral target that interacts with NS3 and viral RNA within the replication complex assembly. Biochemical and cell-based evidence indicate that targeting cavity B may lead to dual RdRp and NS5–NS3 interaction inhibitors. By ligand-based design around 1H-pyrido[2,1-b][1,3]benzothiazol-1-one (PBTZ) 1, we identified new potent and selective DENV inhibitors that exert dual inhibition of NS5 RdRp and NS3–NS5 interaction, likely through binding cavity B. Resistance studies with compound 4 generated sequence variants in the 3′-untranslated region of RNA while further biochemical experiments demonstrated its ability to block also RNA-NS5 interaction, required for correct RNA synthesis in cells. These findings shed light on the potential mechanism of action for this class of compounds, underlying how PBTZs are very promising lead candidates for further evaluation. |
| Databáze: | OpenAIRE |
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