Pyridobenzothiazolones Exert Potent Anti-Dengue Activity by Hampering Multiple Functions of NS5 Polymerase
Rolando Cannalire Kitti Wing Ki Chan Maria Sole Burali Chin Piaw Gwee Sai Wang Andrea Astolfi Serena Massari Stefano Sabatini Oriana Tabarrin Eloise Mastrangelo
Rolando Cannalire
Kitti Wing Ki Chan
Maria Sole Burali
Chin Piaw Gwee
Sai Wang
Andrea Astolfi
Serena Massari
Stefano Sabatini
Oriana Tabarrin
Eloise Mastrangelo
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Abstract
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.
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Source Title
ACS Medicinal Chemistry Letters
Publisher
American Chemical Society
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Date
2020-03-19
DOI
10.1021/acsmedchemlett.9b00619
Type
Article