Antiviral activity of stachyflin on influenza A viruses of different hemagglutinin subtypes.
Antiviral activity of stachyflin on influenza A viruses of different hemagglutinin subtypes.
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DOI：
10.1186/1743-422x-10-118
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发表时间：
2013-04-16
期刊：
影响因子：
4.8
通讯作者：
Kida H
中科院分区：
文献类型：
--
作者：
Motohashi Y;Igarashi M;Okamatsu M;Noshi T;Sakoda Y;Yamamoto N;Ito K;Yoshida R;Kida H
流感病毒的血凝素（HA）是抗病毒药物的可能靶点，因为它在感染的起始中起关键作用。虽然发现天然化合物水苏菌素抑制H1和H2流感病毒在MDCK细胞中的生长，但不抑制H3流感病毒的生长，但尚未评估该化合物对H4-H16流感病毒的抑制活性，并且尚未阐明确切的抑制机制。在MDCK细胞中检测水苏素对H4-H16流感病毒以及H1-H3病毒的抑制活性。为了鉴定病毒对该化合物的易感性的因素，在MDCK细胞中选择水苏碱抗性病毒并用于计算机对接模拟。发现水苏素除了对H1和H2亚型流感病毒的抗病毒活性外，还抑制H5和H6亚型病毒以及A（H1N1）pdm 09病毒在MDCK细胞中的复制。水苏菌素还抑制了感染A/WSN/1933（H1N1）和A/chicken/茨木/1/2005（H5 N2）的小鼠肺中的病毒生长。在抗水苏素病毒的HA 2亚基上发现了氨基酸残基的取代。对接模拟表明D37、K51、T107和K121负责构建用于化合物结合的空腔。另外，水苏素敏感株与不敏感株HA空腔的三维结构也不同。发现水苏素对A（H1N1）pdm 09、H5和H6病毒的抗病毒活性，并鉴定了水苏素在HA上的潜在结合口袋。本研究结果为开发高效广谱的HA抑制剂提供了参考。
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. 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. 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. 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.