Superior inhibition of influenza virus hemagglutinin-mediated fusion by indole-substituted spirothiazolidinones.

ID: ALA4609985

Journal: Bioorg Med Chem

Title: Superior inhibition of influenza virus hemagglutinin-mediated fusion by indole-substituted spirothiazolidinones.

Authors: Cihan-Üstündağ G, Zopun M, Vanderlinden E, Ozkirimli E, Persoons L, Çapan G, Naesens L.

Abstract: 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 EC₅₀ 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.

CiteXplore: 31753804

DOI: 10.1016/j.bmc.2019.115130

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