Monomeric inhibitors of influenza neuraminidase enhance the hemagglutination inhibition activities of polyacrylamides presenting multiple C-sialoside groups
Monomeric inhibitors of influenza neuraminidase enhance the hemagglutination inhibition activities of polyacrylamides presenting multiple C-sialoside groups
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DOI：
10.1016/s1074-5521(96)90285-9
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发表时间：
1996-02-01
影响因子：
--
通讯作者：
Whitesides, GM
中科院分区：
文献类型：
--
作者：
Choi, SK;Mammen, M;Whitesides, GM
背景资料：流感病毒使用血凝素（HA）阵列与细胞表面的唾液酸部分结合;红细胞通过该机制交联导致血凝。许多含有多个唾液酸（Neu 5Ac）基团作为侧链的合成聚合物是该过程的有效抑制剂。抑制可能是由于两种机制：抑制剂的多个Neu 5Ac侧链与病毒表面的多个HA位点的多价结合，或通过一层吸附的、水膨胀的聚合物对病毒颗粒进行空间稳定，从而防止粘附到红细胞上。这两种效果之间的平衡是尚未knowed.Results：聚丙烯酰胺与多个C-唾液酸苷（PA（Neu 5Ac））是2-20倍更有效的抑制剂病毒介导的血细胞凝集时，在Neu 2 en-NH 2，一个有效的单体抑制剂流感神经氨酸酶（NA）的存在下进行测定。NA的单体抑制剂的能力，以提高在本试验中的血凝抑制与NA的单体的亲和力。结论：Wie提出，NA的抑制剂的行为通过竞争与PA（Neu 5Ac）的C-唾液酸苷结合的NA的活性位点。Neu 5Ac的竞争性置换引起吸附到病毒的聚合物凝胶层的膨胀，增强其抑制作用。这项研究提供了一个例子，针对两种不同的蛋白质的活性位点的两个配体之间的协同作用，并加强了这样的结论，空间稳定性是重要的多价抑制剂的活性。
Background: Influenza Viruses use hemagglutinin (HA) arrays to bind to sialic acid moieties on the surface of cells; crosslinking of erythrocytes by this mechanism leads to hemagglutination. A number of synthetic polymers containing multiple sialic acid (Neu5Ac) groups as side chains are potent inhibitors of this process. Inhibition may be due to two mechanisms: polyvalent binding of the inhibitor's multiple Neu5Ac side chains to multiple HA sites on the viral surface, or steric stabilization of the viral particle by a layer of the adsorbed, water-swollen polymer, which prevents adhesion to the erythrocyte. The balance between these two effects is not yet known.Results: Polyacrylamides with multiple C-sialosides (PA(Neu5Ac)) were 2-20 fold more effective as inhibitors of virally mediated hemagglutination when assayed in the presence of Neu2en-NH2, a potent monomeric inhibitor of influenza neuraminidase (NA). The ability of monomeric inhibitors of NA to enhance the inhibition of hemagglutination in this assay correlated with the affinity of the monomer for NA.Conclusions: Wie propose that inhibitors of NA act by competing with the C-sialosides of PA(Neu5Ac) for binding to the active sites of the NA. Competitive displacement of Neu5Ac causes an expansion of the layer of polymeric gel adsorbed to the virus, enhancing its inhibitory effect. This study provides an example of synergy between two Ligands directed toward the active sites of two different proteins, and reinforces the conclusion that steric stabilization is important for the activity of polyvalent inhibitors.