Structure-based identification of an inducer of the low-pH conformational change in the influenza virus hemagglutinin: Irreversible inhibition of infectivity
Structure-based identification of an inducer of the low-pH conformational change in the influenza virus hemagglutinin: Irreversible inhibition of infectivity
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DOI：
10.1128/jvi.71.11.8808-8820.1997
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发表时间：
1997-11-01
影响因子：
5.4
通讯作者：
White, JM
中科院分区：
文献类型：
--
作者：
Hoffman, LR;Kuntz, ID;White, JM
过去采用基于结构的方法来设计流感病毒血凝素（HA）中融合诱导构象变化的抑制剂的努力产生了小苯醌和氢醌家族。这些中最有效的是叔丁基氢醌（TBHQ），其以微摩尔范围内的50%抑制浓度抑制来自株X：31流感病毒的HA中的构象变化和组织培养细胞中的病毒感染性（D. L.博迪安河B。山崎河L. Buswell，J.F.斯特恩斯白色和我。D. Kuntz，Biochemistry 32：2967-2978，1993）。开始了一项新的基于结构的抑制剂设计研究，其中涉及（i）HA胞外域的最近改进的晶体结构（2.1埃分辨率），（ii）对构象变化的新见解，以及（iii）分子对接程序DOCK的改进。因此，我们确定了HA介导的膜融合的新抑制剂。与TBHQ一样，这些分子中的大多数抑制构象变化。然而，其中一种新化合物促进而不是抑制HA构象变化。尽管如此，促进剂二碘荧光素抑制HA介导的膜融合和不可逆的感染性。我们进一步表征了来自两种搜索的抑制剂对HA的构象变化和膜融合活性以及对病毒感染性的影响。我们还分离和表征了几种对每类抑制剂具有抗性的突变体。HA介导的膜融合，抗流感病毒治疗，和基于结构的抑制剂设计的影响，我们的研究结果进行了讨论。
Past efforts to employ a structure-based approach to design an inhibitor of the fusion-inducing conformational change in the influenza virus hemagglutinin (HA) yielded a family of small benzoquinones and hydroquinones, The most potent of these, tert-butyl hydroquinone (TBHQ), inhibits both the conformational change in HA from strain X:31 influenza virus and viral infectivity in tissue culture cells with 50% inhibitory concentrations in the micromolar range (D. L. Bodian, R. B. Yamasaki, R. L. Buswell, J. F. Stearns, J. M. White, and I. D. Kuntz, Biochemistry 32:2967-2978, 1993). A new structure-based inhibitor design search was begun which involved (i) the recently refined crystal structure (2.1-Angstrom resolution) of the HA ectodomain, (ii) new insights into the conformational change, and (iii) improvements in the molecular docking program, DOCK. As a result, we identified new inhibitors of HA-mediated membrane fusion. Like TBHQ, most of these molecules inhibit the conformational change, One of the new compounds, however, facilitates rather than inhibits the HA conformational change, Nonetheless, the facilitator, diiodofluorescein, inhibits HA-mediated membrane fusion and, irreversibly, infectivity. We further characterized the effects of inhibitors from both searches on the conformational change and membrane fusion activity of HA as well as on viral infectivity. We also isolated and characterized several mutants resistant to each class of inhibitor. The implications of our results for HA-mediated membrane fusion, anti-influenza virus therapy, and structure-based inhibitor design are discussed.