Salicylamide scaffold targets flavivirus polymerase in West Nile and Zika models
- A salicylanilide hit was identified as an inhibitor of the West Nile virus polymerase, and medicinal chemistry optimization produced an analogue, S7, with antiviral activity in cell culture at low cytotoxicity.
- S7 and related compounds also blocked Zika virus polymerase and showed cellular antiviral effects.
- Versus niclosamide, S7 had milder mitochondrial effects, less cytotoxicity and no apoptosis induction.
- Modelling and mutagenesis point to binding in the conserved N-pocket of the polymerase.
💡 Points
S7's cleaner mitochondrial profile versus niclosamide is the data to chase: salicylanilides are classic protonophore frequent hitters, so RdRp inhibition decoupled from uncoupling is what makes the scaffold usable. N-pocket binding rests on docking plus mutagenesis, though, and without a co-crystal I wouldn't trust the SAR yet. A conserved pocket and easy amide chemistry make pan-flavivirus follow-up cheap.