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

Gökçe Cihan-Üstündağ; Muhammet Zopun; Evelien Vanderlinden; Elif Ozkirimli; Leentje Persoons; Gültaze Çapan; Lieve Naesens

doi:10.1016/j.bmc.2019.115130

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. Epub 2019 Nov 8.

Authors

Gökçe Cihan-Üstündağ¹, Muhammet Zopun¹, Evelien Vanderlinden², Elif Ozkirimli³, Leentje Persoons², Gültaze Çapan¹, Lieve Naesens⁴

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: lieve.naesens@kuleuven.be.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Dogs
Dose-Response Relationship, Drug
Hemagglutinin Glycoproteins, Influenza Virus / drug effects*
Humans
Hydrogen-Ion Concentration
Indoles / chemistry
Indoles / pharmacology*
Influenza A Virus, H3N2 Subtype / drug effects*
Influenza, Human / drug therapy*
Madin Darby Canine Kidney Cells / drug effects
Madin Darby Canine Kidney Cells / virology
Microbial Sensitivity Tests
Molecular Docking Simulation
Molecular Structure
Protein Refolding / drug effects
Spiro Compounds / chemistry
Spiro Compounds / pharmacology*
Structure-Activity Relationship
Thiazolidines / chemistry
Thiazolidines / pharmacology*

Substances

Antiviral Agents
Hemagglutinin Glycoproteins, Influenza Virus
Indoles
Spiro Compounds
Thiazolidines
indole