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Antiviral activity of stachyflin on influenza A viruses of different hemagglutinin subtypes

Yurie Motohashi1, Manabu Igarashi2, Masatoshi Okamatsu1, Takeshi Noshi3, Yoshihiro Sakoda1, Naoki Yamamoto1, Kimihito Ito2, Ryu Yoshida3 and Hiroshi Kida12*

Author Affiliations

1 Department of Disease Control, Laboratory of Microbiology, Graduate School of Veterinary Medicine, Hokkaido University, Kita-18 Nishi-9, Sapporo 060-0818, Japan

2 Division of Bioinformatics, Research Center for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan

3 Discovery Research Laboratories, Shionogi & Co., Ltd., Settsu, Osaka 566-0022, Japan

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Virology Journal 2013, 10:118  doi:10.1186/1743-422X-10-118

Published: 16 April 2013

Abstract

Background

The hemagglutinin (HA) of influenza viruses is a possible target for antiviral drugs because of its key roles in the initiation of infection. Although it was found that a natural compound, Stachyflin, inhibited the growth of H1 and H2 but not H3 influenza viruses in MDCK cells, inhibitory activity of the compound has not been assessed against H4-H16 influenza viruses and the precise mechanism of inhibition has not been clarified.

Methods

Inhibitory activity of Stachyflin against H4-H16 influenza viruses, as well as H1-H3 viruses was examined in MDCK cells. To identify factors responsible for the susceptibility of the viruses to this compound, Stachyflin-resistant viruses were selected in MDCK cells and used for computer docking simulation.

Results

It was found that in addition to antiviral activity of Stachyflin against influenza viruses of H1 and H2 subtypes, it inhibited replication of viruses of H5 and H6 subtypes, as well as A(H1N1)pdm09 virus in MDCK cells. Stachyflin also inhibited the virus growth in the lungs of mice infected with A/WSN/1933 (H1N1) and A/chicken/Ibaraki/1/2005 (H5N2). Substitution of amino acid residues was found on the HA2 subunit of Stachyflin-resistant viruses. Docking simulation indicated that D37, K51, T107, and K121 are responsible for construction of the cavity for the binding of the compound. In addition, 3-dimensional structure of the cavity of the HA of Stachyflin-susceptible virus strains was different from that of insusceptible virus strains.

Conclusion

Antiviral activity of Stachyflin was found against A(H1N1)pdm09, H5, and H6 viruses, and identified a potential binding pocket for Stachyflin on the HA. The present results should provide us with useful information for the development of HA inhibitors with more effective and broader spectrum.

Keywords:
Stachyflin; Anti-influenza drug; HA inhibitor; Docking model