2. Academic Validation
  3. Superior inhibition of influenza virus hemagglutinin-mediated fusion by indole-substituted spirothiazolidinones

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

  • Bioorg Med Chem. 2020 Jan 1;28(1):115130. doi: 10.1016/j.bmc.2019.115130.
Gökçe Cihan-Üstündağ 1,  Muhammet Zopun 1,  Evelien Vanderlinden 2,  Elif Ozkirimli 3,  Leentje Persoons 2,  Gültaze Çapan 1,  Lieve Naesens 4
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Istanbul University, Istanbul 34116, Turkey.
  • 2 Rega Institute for Medical Research, KU Leuven, Department of Microbiology, Immunology and Transplantation, B-3000 Leuven, Belgium.
  • 3 Chemical Engineering Department, Bogazici University, Istanbul 34342, Turkey.
  • 4 Rega Institute for Medical Research, KU Leuven, Department of Microbiology, Immunology and Transplantation, B-3000 Leuven, Belgium. Electronic address: [email protected].
PMID: 31753804 DOI: 10.1016/j.bmc.2019.115130
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.

Keywords

Antiviral; Fusion; Hemagglutinin; In silico; Indole; Influenza virus; Inhibitor; Spirothiazolidinone.

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