tetano
Editor, Senior Moderator
Bioorg Med Chem. 2019 Nov 8:115130. doi: 10.1016/j.bmc.2019.115130. [Epub ahead of print] [h=1]Superior inhibition of influenza virus hemagglutinin-mediated fusion by indole-substituted spirothiazolidinones.[/h]
Cihan-?st?ndağ G[SUP]1[/SUP], Zopun M[SUP]1[/SUP], Vanderlinden E[SUP]2[/SUP], Ozkirimli E[SUP]3[/SUP], Persoons L[SUP]2[/SUP], ?apan G[SUP]1[/SUP], Naesens L[SUP]4[/SUP].
[h=3]Author information[/h] 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.
[h=3]Abstract[/h] 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 EC[SUB]50[/SUB] 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.
Copyright ? 2019 Elsevier Ltd. All rights reserved.
[h=4]KEYWORDS:[/h] Antiviral; Fusion; Hemagglutinin; In silico; Indole; Influenza virus; Inhibitor; Spirothiazolidinone
PMID: 31753804 DOI: 10.1016/j.bmc.2019.115130
Cihan-?st?ndağ G[SUP]1[/SUP], Zopun M[SUP]1[/SUP], Vanderlinden E[SUP]2[/SUP], Ozkirimli E[SUP]3[/SUP], Persoons L[SUP]2[/SUP], ?apan G[SUP]1[/SUP], Naesens L[SUP]4[/SUP].
[h=3]Author information[/h] 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.
[h=3]Abstract[/h] 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 EC[SUB]50[/SUB] 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.
Copyright ? 2019 Elsevier Ltd. All rights reserved.
[h=4]KEYWORDS:[/h] Antiviral; Fusion; Hemagglutinin; In silico; Indole; Influenza virus; Inhibitor; Spirothiazolidinone
PMID: 31753804 DOI: 10.1016/j.bmc.2019.115130