INHIBITION OF THE FUSION-INDUCING CONFORMATIONAL CHANGE OF INFLUENZA HEMAGGLUTININ BY BENZOQUINONES AND HYDROQUINONES
INHIBITION OF THE FUSION-INDUCING CONFORMATIONAL CHANGE OF INFLUENZA HEMAGGLUTININ BY BENZOQUINONES AND HYDROQUINONES
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DOI：
10.1021/bi00063a007
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发表时间：
1993-03-30
期刊：
影响因子：
2.9
通讯作者：
KUNTZ, ID
中科院分区：
文献类型：
--
作者：
BODIAN, DL;YAMASAKI, RB;KUNTZ, ID
流感血凝素（HA）经历病毒进入所需的构象变化。重排包括暴露融合肽，即埋在天然蛋白质的三聚体界面中的疏水片段。由于融合肽的释放触发了对病毒复制至关重要的膜融合事件，因此抑制融合肽的暴露应可预防感染。我们推断，与HA结合并稳定其非融合构象的小分子将阻断病毒活性。计算机辅助方法用于选择假定的HA配体。所选化合物之一，4A，5，8，8A-四氢-5，8-亚甲基-1，4-萘醌，阻止X31 HA转化为被α-融合肽抗血清识别的构象。该化合物的几种衍生物，包括苯醌和氢醌，也显示出抑制作用。测试的最有效的化合物具有1至20 μ M的IC 50。代表性化合物还在体外抑制病毒诱导的合胞体形成、HA介导的溶血和病毒感染性。这些抑制剂是开发抗病毒药物的重要线索，并可作为HA构象变化机制的探针。
Influenza hemagglutinin (HA) undergoes a conformational change that is required for viral entry. The rearrangement includes exposure of the fusion peptide, a hydrophobic segment buried in the trimer interface of the native protein. Since fusion peptide release triggers the membrane fusion event crucial for viral replication, inhibition of fusion peptide exposure should prevent infection. We reasoned that small molecules that bind to HA and stabilize its nonfusogenic conformation would block viral activity. A computer-assisted method was used to select putative HA ligands. One of the selected compounds, 4A,5,8,8A-tetrahydro-5,8-methano-1,4-naphthoquinone, prevented the conversion of X31 HA to a conformation recognized by alpha-fusion peptide antisera. Several derivatives of this compound, including both benzoquinones and hydroquinones, also showed inhibition. The most effective compounds tested have IC50s between 1 and 20 muM. Representative compounds also inhibited virus-induced syncytia formation, HA-mediated hemolysis, and viral infectivity in vitro. The inhibitors are attractive leads for the development of antiviral drugs and can serve as probes of the mechanism of the conformational change of HA.