A Sulfonozanamivir Analogue Has Potent Anti-influenza Virus Activity

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Author(s)
Hadhazi, Adam
Li, Linghui
Bailly, Benjamin
Maggioni, Andrea
Martin, Gael
Dirr, Larissa
Dyason, Jeffrey C
Thomson, Robin J
Gao, George F
Borbas, Aniko
Ve, Thomas
Pascolutti, Mauro
von Itzstein, Mark
Griffith University Author(s)
Year published
2018
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Influenza virus infection continues to cause significant, often severe, respiratory illness worldwide. A validated target for the development of anti‐influenza agents is the virus surface protein sialidase. In the current study, we have discovered a highly potent inhibitor of influenza virus sialidase, based on a novel sialosyl sulfonate template. The synthesised 3‐guanidino sialosyl α‐sulfonate, a sulfonozanamivir analogue, inhibits viral replication in vitro at the nanomolar level, comparable to that of the anti‐influenza drug zanamivir. Using protein X‐ray crystallography we show that the sialosyl α‐sulfonate template ...
View more >Influenza virus infection continues to cause significant, often severe, respiratory illness worldwide. A validated target for the development of anti‐influenza agents is the virus surface protein sialidase. In the current study, we have discovered a highly potent inhibitor of influenza virus sialidase, based on a novel sialosyl sulfonate template. The synthesised 3‐guanidino sialosyl α‐sulfonate, a sulfonozanamivir analogue, inhibits viral replication in vitro at the nanomolar level, comparable to that of the anti‐influenza drug zanamivir. Using protein X‐ray crystallography we show that the sialosyl α‐sulfonate template binds within the sialidase active site in a 1C4 chair conformation. The C1‐sulfonate moiety forms crucial and strong‐binding interactions with the active site's triarginyl cluster, while the 3‐guanidino moiety interacts significantly with conserved active site residues. This sulfonozanamivir analogue provides a new direction in anti‐influenza virus drug development.
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View more >Influenza virus infection continues to cause significant, often severe, respiratory illness worldwide. A validated target for the development of anti‐influenza agents is the virus surface protein sialidase. In the current study, we have discovered a highly potent inhibitor of influenza virus sialidase, based on a novel sialosyl sulfonate template. The synthesised 3‐guanidino sialosyl α‐sulfonate, a sulfonozanamivir analogue, inhibits viral replication in vitro at the nanomolar level, comparable to that of the anti‐influenza drug zanamivir. Using protein X‐ray crystallography we show that the sialosyl α‐sulfonate template binds within the sialidase active site in a 1C4 chair conformation. The C1‐sulfonate moiety forms crucial and strong‐binding interactions with the active site's triarginyl cluster, while the 3‐guanidino moiety interacts significantly with conserved active site residues. This sulfonozanamivir analogue provides a new direction in anti‐influenza virus drug development.
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Journal Title
ChemMedChem
Volume
13
Issue
8
Copyright Statement
© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. This is the peer reviewed version of the following article: A Sulfonozanamivir Analogue Has Potent Anti-influenza Virus Activity, ChemMedChem, Volume 13, Issue 8, April 23, 2018, Pages 785-789, which has been published in final form at 10.1002/cmdc.201800092. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving (http://olabout.wiley.com/WileyCDA/Section/id-828039.html)
Subject
Medicinal and biomolecular chemistry
Medicinal and biomolecular chemistry not elsewhere classified
Organic chemistry
Pharmacology and pharmaceutical sciences