posted on 2020-03-23, 13:39authored byRolando 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 Manfroni
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.