Bodian D L, Yamasaki R B, Buswell R L, Stearns J F, White J M, Kuntz I D
Department of Biochemistry and Biophysics, University of California, San Francisco 94143-0448.
Biochemistry. 1993 Mar 30;32(12):2967-78. doi: 10.1021/bi00063a007.
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 microM. 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.
流感血凝素（HA）会发生一种病毒进入所必需的构象变化。这种重排包括融合肽的暴露，融合肽是一个埋在天然蛋白质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，抑制融合肽的暴露应该可以预防感染。我们推测，与HA结合并稳定其非融合构象的小分子会阻断病毒活性。一种计算机辅助方法被用于选择假定的HA配体。所选择的化合物之一，4A,5,8,8A-四氢-5,8-亚甲基-1,4-萘醌，阻止了X31 HA转变为被α-融合肽抗血清识别的构象。该化合物的几种衍生物，包括苯醌和对苯二酚，也显示出抑制作用。测试的最有效化合物的IC50在1至20微摩尔之间。代表性化合物在体外也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有吸引力的先导物，并且可以作为HA构象变化机制的探针。
