Hemagglutinin mutations responsible for the binding of highly pathogenic influenza virus to human type receptors and influenza drug discovery.

期间（2008年4月）。2012年3月)，我们阐明了高致病性流感病毒（H5N1亚型）与人型受体结合的血凝素（HA）突变的几个新机制，并在流感药物发现方面取得了进展。(1)我们在从“患者”和“鸟类”中分离的高致病性禽流感病毒（H5N1亚型）的HA（H5）尖峰中发现了几种氨基酸替换，这些氨基酸替换增加了它们的人型受体（neu5ac α 2,6 gal）特异性，这些亚谱系的病毒在人呼吸道中的附着性和传染性增强。我们还鉴定了一种实验性重组H5 HA/H1N1病毒。包括H5 HA（来自H5N1病毒），仅有4个氨基酸突变，其余7个基因片段来自2009年H1N1大流行病毒。这显示出与人类受体的附着增加，并且能够“在雪貂模型中通过液滴传播”。我们的发现可能有助于促进我们对哺乳动物中禽流感病毒传播的机制和进化途径的理解。(2)对猪、狗、猫、鸡胚蛋等几种H5N1宿主动物靶细胞的H5N1病毒HA受体n链进行了精细化学结构的测定。(3)我们开发了超过15种新的合成和天然化合物，可以抑制人流感病毒受体的结合、复制和从感染的宿主细胞出芽。

During the period(April, 2008.March 2012) of this grant, we clarified several new mechanisms on the hemagglutinin(HA) mutations responsible for the binding of highly pathogenic influenza virus(H5N1 subtype) to human type receptors and got progress on the drug discovery for influenza.(1) We identified several type of amino acid substitutions in the HA(H5) spike of highly pathogenic avian influenza viruses(H5N1 subtype) isolated from not only "patients" but also from "birds" that increase their human-type receptor(Neu5Acα2, 6Gal) specificity Viruses in those sublineages exhibited increased attachment and infectivity in the human respiratory tract. We also identified an experimental reassortant H5 HA/H1N1 virus. comprising H5 HA(from an H5N1 virus) with only four amino acid mutations and the remaining seven gene segments from a 2009 pandemic H1N1 virus. that exhibited increased attachment to the human type receptor and was capable of "droplet transmission in a ferret model". Our findings may help to advance our understanding of the mechanisms and evolutionary pathways that contribute to avian influenza virus transmission in mammals.(2) We also determined the fine chemical structures of H5N1 viral HA receptor N-linked sialo sugar chains of several target cells of H5N1 host animals, such as pig, dog, cat, embryonated chicken eggs.(3) We developed more than 15 new synthetic and native compounds which inhibit human influenza virus receptor binding, replication and budding from the infected host cells.