tetano
Editor, Senior Moderator
ChemMedChem. 2018 Feb 17. doi: 10.1002/cmdc.201800092. [Epub ahead of print]
[h=1]A Sulfonozanamivir Analogue has Potent Anti-influenza Virus Activity.[/h] Hadh?zi ?[SUP]1[/SUP], Li L[SUP]2[/SUP], Bailly B[SUP]2[/SUP], Maggioni A[SUP]2[/SUP], Martin G[SUP]2[/SUP], Dirr L[SUP]2[/SUP], Dyason J[SUP]2[/SUP], Thomson R[SUP]2[/SUP], Gao G[SUP]3[/SUP], Borb?s A[SUP]1[/SUP], Ve T[SUP]2[/SUP], Pascolutti M[SUP]2[/SUP], von Itzstein M[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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.
[h=4]KEYWORDS:[/h] Antiviral agent; Influenza virus; sialic acid; sialidase; sulfonate
PMID: 29453852 DOI: 10.1002/cmdc.201800092
[h=1]A Sulfonozanamivir Analogue has Potent Anti-influenza Virus Activity.[/h] Hadh?zi ?[SUP]1[/SUP], Li L[SUP]2[/SUP], Bailly B[SUP]2[/SUP], Maggioni A[SUP]2[/SUP], Martin G[SUP]2[/SUP], Dirr L[SUP]2[/SUP], Dyason J[SUP]2[/SUP], Thomson R[SUP]2[/SUP], Gao G[SUP]3[/SUP], Borb?s A[SUP]1[/SUP], Ve T[SUP]2[/SUP], Pascolutti M[SUP]2[/SUP], von Itzstein M[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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.
[h=4]KEYWORDS:[/h] Antiviral agent; Influenza virus; sialic acid; sialidase; sulfonate
PMID: 29453852 DOI: 10.1002/cmdc.201800092