Department of Chemistry, University of Hamburg , 20146 Hamburg, Germany.
J Am Chem Soc. 2014 Jan 15;136(2):783-8. doi: 10.1021/ja410918a. Epub 2014 Jan 7.
Influenza virus attaches itself to sialic acids on the surface of epithelial cells of the upper respiratory tract of the host using its own protein hemagglutinin. Species specificity of influenza virus is determined by the linkages of the sialic acids. Birds and humans have α2-3 and α2-6 linked sialic acids, respectively. Viral hemagglutinin is a homotrimeric receptor, and thus, tri- or oligovalent ligands should have a high binding affinity. We describe the in silico design, chemical synthesis and binding analysis of a trivalent glycopeptide mimetic. This compound binds to hemagglutinin H5 of avian influenza with a dissociation constant of K(D) = 446 nM and an inhibitory constant of K(I) = 15 μM. In silico modeling shows that the ligand should also bind to hemagglutinin H7 of the virus that causes the current influenza outbreak in China. The trivalent glycopeptide mimetic and analogues have the potential to block many different influenza viruses.
流感病毒利用自身的血凝素蛋白附着在宿主上呼吸道的上皮细胞表面的唾液酸上。流感病毒的物种特异性由唾液酸的连接方式决定。鸟类和人类分别具有α2-3 和 α2-6 连接的唾液酸。病毒血凝素是三聚体受体，因此，三价或寡价配体应该具有高结合亲和力。我们描述了一种三价糖肽模拟物的计算机设计、化学合成和结合分析。该化合物与禽流感血凝素 H5 的解离常数为 K(D) = 446 nM，抑制常数为 K(I) = 15 μM。计算机建模表明，该配体也应该与引起中国当前流感爆发的病毒的血凝素 H7 结合。三价糖肽模拟物及其类似物有可能阻止许多不同的流感病毒。
