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

Yurie Motohashi,Kimihito Ito,Hiroshi Kida,Takeshi Noshi,Naoki Yamamoto,Ryu Yoshida,Yoshihiro Sakoda,Manabu Igarashi,Masatoshi Okamatsu

doi:10.1186/1743-422x-10-118

Yurie Motohashi, Kimihito Ito + Show 7 more

Open Access

https://doi.org/10.1186/1743-422x-10-118

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Abstract

BackgroundThe 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.MethodsInhibitory 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.ResultsIt 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.ConclusionAntiviral 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.

Highlights

The hemagglutinin (HA) of influenza viruses is a possible target for antiviral drugs because of its key roles in the initiation of infection
The antiviral effects were evaluated in various concentrations of Stachyflin up to 6.50 μM by virus-induced cytopathic effects (CPE)
Stachyflin inhibited the replication of H1 including A (H1N1)pdm09 virus, H2, H5, and H6 subtype influenza virus strains, but not that of the other subtype strains

Summary

Introduction

The hemagglutinin (HA) of influenza viruses is a possible target for antiviral drugs because of its key roles in the initiation of infection. Hemagglutinin (HA) is a surface glycoprotein of influenza A virus, and is a possible target of antiviral drugs because of its key roles in the initiation of infection. Several studies have identified compounds which inhibit viral infection by blocking the binding of the HA to sialic acid receptor on the host cell surface (cyanovirin-N and trisphenol-sialyllactose) or fusion step (TBHQ, BMY27709, CL-385319, and N-carboxamide) [8,9,10,11,12]; for many of these inhibitors, the antiviral spectrum is limited to the HA of certain subtypes, so that they have not been used clinically. To develop more effective HA inhibitors, further investigations of these HA inhibitors and the analysis of the attachment and fusion steps of influenza virus infection in the host cells are needed

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