A Sulfonozanamivir Analogue Has Potent Anti‐influenza Virus Activity |
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Authors: | Ádám Hadházi Linghui Li Dr. Benjamin Bailly Dr. Andrea Maggioni Gael Martin Dr. Larissa Dirr Jeffrey C. Dyason Dr. Robin J. Thomson Prof. George F. Gao Prof. Anikó Borbás Dr. Thomas Ve Dr. Mauro Pascolutti Prof. Mark von Itzstein |
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Affiliation: | 1. Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, Australia;2. Department of Pharmaceutical Chemistry, University of Debrecen, Debrecen, Hungary;3. University of Chinese Academy of Sciences, Beijing, China;4. Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China |
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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. |
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Keywords: | antiviral agents influenza virus sialic acid sialidase sulfonates |
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