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
  • 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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