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Pyridobenzothiazolones Exert Potent Anti-Dengue Activity by Hampering Multiple Functions of NS5 Polymerase
journal contribution
posted on 2020-03-23, 13:39 authored by Rolando Cannalire, Kitti Wing Ki Chan, Maria Sole Burali, Chin Piaw Gwee, Sai Wang, Andrea Astolfi, Serena Massari, Stefano Sabatini, Oriana Tabarrini, Eloise Mastrangelo, Maria Letizia Barreca, Violetta Cecchetti, Subhash G. Vasudevan, Giuseppe ManfroniTreatment 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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compound 4NS 3RNA synthesiscell-based evidencePyridobenzothiazolones Exert Potent...PBTZflavivirus infectionssequence variantsresistance studiesRNA-NS 5 interactionligand-based designdengue viruscavity B1 HNS 5 Polymerase TreatmentDENV inhibitorsflaviviral NS 5 RNA-dependent RNA p...Hampering Multiple Functionsbinding cavity BNS 5 RdRp
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