A Sulfonozanamivir Analogue Has Potent Anti-influenza Virus Activity

Ádám Hadházi, Linghui Li, Benjamin Bailly, Andrea Maggioni, Gael Martin, Larissa Dirr, Jeffrey C. Dyason, Robin J. Thomson, George F. Gao, A. Borbás, Thomas Ve, Mauro Pascolutti, Mark von Itzstein

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)785-789
Number of pages5
JournalChemMedChem
Volume13
Issue number8
DOIs
Publication statusPublished - Apr 23 2018

Fingerprint

Neuraminidase
Orthomyxoviridae
Viruses
Catalytic Domain
Human Influenza
Zanamivir
X Ray Crystallography
Virus Diseases
Pharmaceutical Preparations
X ray crystallography
Membrane Proteins
Conformations
Proteins

Keywords

  • antiviral agents
  • influenza virus
  • sialic acid
  • sialidase
  • sulfonates

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

Cite this

Hadházi, Á., Li, L., Bailly, B., Maggioni, A., Martin, G., Dirr, L., ... von Itzstein, M. (2018). A Sulfonozanamivir Analogue Has Potent Anti-influenza Virus Activity. ChemMedChem, 13(8), 785-789. https://doi.org/10.1002/cmdc.201800092

A Sulfonozanamivir Analogue Has Potent Anti-influenza Virus Activity. / Hadházi, Ádám; Li, Linghui; Bailly, Benjamin; Maggioni, Andrea; Martin, Gael; Dirr, Larissa; Dyason, Jeffrey C.; Thomson, Robin J.; Gao, George F.; Borbás, A.; Ve, Thomas; Pascolutti, Mauro; von Itzstein, Mark.

In: ChemMedChem, Vol. 13, No. 8, 23.04.2018, p. 785-789.

Research output: Contribution to journalArticle

Hadházi, Á, Li, L, Bailly, B, Maggioni, A, Martin, G, Dirr, L, Dyason, JC, Thomson, RJ, Gao, GF, Borbás, A, Ve, T, Pascolutti, M & von Itzstein, M 2018, 'A Sulfonozanamivir Analogue Has Potent Anti-influenza Virus Activity', ChemMedChem, vol. 13, no. 8, pp. 785-789. https://doi.org/10.1002/cmdc.201800092
Hadházi Á, Li L, Bailly B, Maggioni A, Martin G, Dirr L et al. A Sulfonozanamivir Analogue Has Potent Anti-influenza Virus Activity. ChemMedChem. 2018 Apr 23;13(8):785-789. https://doi.org/10.1002/cmdc.201800092
Hadházi, Ádám ; Li, Linghui ; Bailly, Benjamin ; Maggioni, Andrea ; Martin, Gael ; Dirr, Larissa ; Dyason, Jeffrey C. ; Thomson, Robin J. ; Gao, George F. ; Borbás, A. ; Ve, Thomas ; Pascolutti, Mauro ; von Itzstein, Mark. / A Sulfonozanamivir Analogue Has Potent Anti-influenza Virus Activity. In: ChemMedChem. 2018 ; Vol. 13, No. 8. pp. 785-789.
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