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ChemMedChem. 2018 Feb 17. doi: 10.1002/cmdc.201800092. [Epub ahead of print]
A Sulfonozanamivir Analogue has Potent Anti-influenza Virus Activity.
Hadh?zi ?1, Li L2, Bailly B2, Maggioni A2, Martin G2, Dirr L2, Dyason J2, Thomson R2, Gao G3, Borb?s A1, Ve T2, Pascolutti M2, von Itzstein M4.
Author information
Abstract
Influenza virus infection continues to cause significant, often severe, respiratory illness worldwide. A validated target for development of anti-influenza agents is the viral 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 virus replication in vitro at a nanomolar level, comparable to that of anti-influenza drug zanamivir. Using protein X-ray crystallography we show that the sialosyl α-sulfonate template orients within the sialidase active site in a ?C₄ chair conformation. The C1-sulfonate moiety forms crucial and strong-binding interactions with the active site's triarginyl cluster, while the 3-guanidino moiety significantly interacts with conserved active site residues. This sulfonozanamivir analogue provides a new direction in anti-influenza virus drug development.
KEYWORDS:
Antiviral agent; Influenza virus; sialic acid; sialidase; sulfonate
PMID: 29453852 DOI: 10.1002/cmdc.201800092
A Sulfonozanamivir Analogue has Potent Anti-influenza Virus Activity.
Hadh?zi ?1, Li L2, Bailly B2, Maggioni A2, Martin G2, Dirr L2, Dyason J2, Thomson R2, Gao G3, Borb?s A1, Ve T2, Pascolutti M2, von Itzstein M4.
Author information
Abstract
Influenza virus infection continues to cause significant, often severe, respiratory illness worldwide. A validated target for development of anti-influenza agents is the viral 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 virus replication in vitro at a nanomolar level, comparable to that of anti-influenza drug zanamivir. Using protein X-ray crystallography we show that the sialosyl α-sulfonate template orients within the sialidase active site in a ?C₄ chair conformation. The C1-sulfonate moiety forms crucial and strong-binding interactions with the active site's triarginyl cluster, while the 3-guanidino moiety significantly interacts with conserved active site residues. This sulfonozanamivir analogue provides a new direction in anti-influenza virus drug development.
KEYWORDS:
Antiviral agent; Influenza virus; sialic acid; sialidase; sulfonate
PMID: 29453852 DOI: 10.1002/cmdc.201800092