Inhibition of influenza A virus replication by compounds interfering with the fusogenic function of the viral hemagglutinin
Inhibition of influenza A virus replication by compounds interfering with the fusogenic function of the viral hemagglutinin
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DOI：
10.1128/jvi.73.1.140-151.1999
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发表时间：
1999-01-01
影响因子：
5.4
通讯作者：
Gluzman, Y
中科院分区：
文献类型：
--
作者：
Plotch, SJ;O'Hara, B;Gluzman, Y
通过筛选抗病毒活性的化学文库，鉴定了几种特异性抑制A型流感病毒H1和H2亚型复制的化合物。在单周期感染中，当在感染前或感染后立即加入时，化合物抑制病毒特异性蛋白质合成，但当在30分钟后加入时无效，这表明未包被步骤被阻断。几个独立的突变体病毒的抗化合物的血凝素（IIA）基因的测序揭示了单一的氨基酸变化，簇在HA三聚体的茎区中和附近的HA2融合肽。其中一种化合物，N-取代的哌啶，可以通过计算机辅助分子建模停靠在该区域的口袋中。该化合物阻断了HA的促融合活性，如其抑制感染细胞单层中低pH诱导的细胞-细胞融合所证明的。合成了一种比母体化合物更有效的抑制病毒复制的类似物。它也更有效地阻止其他表现的低pH值诱导的构象变化的HA，包括病毒灭活，病毒诱导的红细胞溶血，和敏感性的HA蛋白水解降解。这两种化合物抑制病毒蛋白质的合成和复制更有效地在细胞感染的病毒突变的M2蛋白比野生型病毒。讨论了M2和IIA之间可能存在的函数关系。
Several compounds that specifically inhibited replication of the H1 and H2 subtypes of influenza virus type A were identified by screening a chemical library for antiviral activity. In single-cycle infections, the compounds inhibited virus-specific protein synthesis when added before or immediately after infection but were ineffective when added 30 min later, suggesting that an uncoating step was blocked. Sequencing of hemagglutinin (IIA) genes of several independent mutant viruses resistant to the compounds revealed single amino acid changes that clustered in the stem region of the HA trimer in and near the HA2 fusion peptide. One of the compounds, an N-substituted piperidine, could be docked in a pocket in this region by computer-assisted molecular modeling. This compound blocked the fusogenic activity of HA, as evidenced by its inhibition of low-pH-induced cell-cell fusion in infected cell monolayers. An analog which was more effective than the parent compound in inhibiting virus replication was synthesized. It was also more effective in blocking other manifestations of the low-pH-induced conformational change in HA including virus inactivation, virus-induced hemolysis of erythrocytes, and susceptibility of the HA to proteolytic degradation. Both compounds inhibited viral protein synthesis and replication more effectively in cells infected with a virus mutated in its M2 protein than with wild-type virus. The possible functional relationship between M2 and IIA suggested by these results is discussed.