Superior inhibition of influenza virus hemagglutinin-mediated fusion by indole-substituted spirothiazolidinones.
Cihan-Üstündağ G, Zopun M, Vanderlinden E, Ozkirimli E, Persoons L, Çapan G, Naesens L.
The influenza virus hemagglutinin (HA) mediates membrane fusion after viral entry by endocytosis. The fusion process requires drastic low pH-induced HA refolding and is prevented by arbidol and tert-butylhydroquinone (TBHQ). We here report a class of superior inhibitors with indole-substituted spirothiazolidinone structure. The most active analogue 5f has an EC<sub>50</sub> value against influenza A/H3N2 virus of 1 nM and selectivity index of almost 2000. Resistance data and in silico modeling indicate that 5f combines optimized fitting in the TBHQ/arbidol HA binding pocket with a capability for endosomal accumulation. Both criteria appear relevant to achieve superior inhibitors of HA-mediated fusion.