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

Tijdschriftbijdrage - Tijdschriftartikel

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.
Tijdschrift: Bioorganic & Medicinal Chemistry
ISSN: 0968-0896
Issue: 1
Volume: 28
Jaar van publicatie:2020
BOF-keylabel:ja
IOF-keylabel:ja
BOF-publication weight:1
CSS-citation score:2
Auteurs:International
Authors from:Higher Education
Toegankelijkheid:Closed