Inhibitors of human immunodeficiency virus type 1 zinc fingers prevent normal processing of Gag precursors and result in the release of noninfectious virus particles
Inhibitors of human immunodeficiency virus type 1 zinc fingers prevent normal processing of Gag precursors and result in the release of noninfectious virus particles
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DOI：
10.1128/jvi.70.9.6180-6189.1996
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发表时间：
1996-09-01
影响因子：
5.4
通讯作者：
Rice, WG
中科院分区：
文献类型：
--
作者：
Turpin, JA;Terpening, SJ;Rice, WG
逆转录病毒核衣壳蛋白的Cys-Xaa（2）-Cys-Xaa（4）-His-Xaa（4）-Cys锌指是主要的抗病毒靶标，因为Cys和His螯合残基的保守性以及在逆转录病毒复制的早期和晚期都绝对需要这些指。我们先前报道了某些二硫键取代的苯甲酰胺（DIBAs）化学修饰指状物的Cys残基，导致人类免疫缺陷病毒1型（HIV-1）复制的抑制（W. G.赖斯，J.G.苏普科湖马尔斯佩河W.小巴克托，D.克兰顿，M.布湖格雷厄姆角A. Schaeffer，J. A. Turpin，J. Domagala，R. Gogliotti，J. P. Bader，S. M.哈利迪湖科伦河C.索德二湖O.亚瑟和L. E.亨德森，科学270：1194-1197，1995）。我们现在研究DIBAs与HIV-1 p7核衣壳蛋白及其pr 55（gag）前体的锌指相互作用的后果。在HIV-1感染的U1细胞中，DIBAs抑制了感染性病毒体的释放，即使在产生病毒体颗粒的条件下，这些颗粒也是非感染性的。DIBAs引起Gag前体的异常加工，并且对加工的抑制作用不是由于抑制HIV-1蛋白酶或Pr 55（gag）肉豆蔻酰化。相反，加工中的缺陷是由于相邻Gag分子的锌指之间形成分子间交联，使得前体不再被HIV-1蛋白酶识别。同样地，DIBAs引起包装成假病毒体的重组Pr 55（gag）之间的分子间交联，从而产生对蛋白酶的作用有抗性的经修饰的前体。因此，DIBAs化学修饰了受感染细胞中突变不耐受的逆转录病毒锌指，中断了蛋白酶介导的病毒体成熟，并最终导致受损病毒体的产生。
The Cys-Xaa(2)-Cys-Xaa(4)-His-Xaa(4)-Cys zinc fingers of retroviral nucleo cap sid proteins are prime antiviral targets because of conservation of the Cys and His chelating residues and the absolute requirement of these fingers in both early and late phases of retroviral replication. We previously reported that certain disulfide-substituted benzamides (DIBAs) chemically modify the Cys residues of the fingers, resulting in inhibition of human immunodeficiency virus type 1 (HIV-1) replication (W. G. Rice, J. G. Supko, L. Malspeis, R. W. Buckheit, Jr., D. Clanton, M. Bu, L. Graham, C. A. Schaeffer, J. A. Turpin, J. Domagala, R. Gogliotti, J. P. Bader, S. M. Halliday, L. Coren, R. C. Sowder II, L. O. Arthur, and L. E. Henderson, Science 270:1194-1197, 1995). We now examine the consequences of the interaction of DIBAs,vith the zinc fingers of the HIV-1 p7 nucleocapsid protein and its pr55(gag) precursor. In HIV-1-infected U1 cells, DIBAs inhibited the release of infectious virions, and even under conditions in which virion particles were produced, the particles were noninfectious. DIBAs caused abnormal processing of Gag precursors, and the inhibitory effect on processing was not due to inhibition of the HIV-1 protease enzyme or Pr55(gag) myristoylation. Rather, the defect in processing was due to the formation of intermolecular cross-linkages among the zinc fingers of adjacent Gag molecules, rendering the precursors no longer recognizable by HIV-1 protease. Likewise, DIBAs caused intermolecular cross-linkage among recombinant Pr55(gag) packaged into pseudovirions, thereby generating modified precursors that were resistant to the action of protease. Thus, DIBAs chemically modified the mutationally intolerant retroviral zinc fingers in infected cells, interrupting protease-mediated maturation of virions and leading ultimately to the production of compromised virions.