Rice W G, Schaeffer C A, Harten B, Villinger F, South T L, Summers M F, Henderson L E, Bess J W, Arthur L O, McDougal J S
Laboratory of Antiviral Drug Mechanisms, Program Resources Inc./DynCorp., National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702.
Nature. 1993 Feb 4;361(6411):473-5. doi: 10.1038/361473a0.
Retroviral nucleocapsid and gag-precursor proteins from all known strains of retroviruses contain one or two copies of an invariant sequence, Cys-X2-Cys-X4-His-X4-Cys, that is populated with zinc in mature particles. Modification of cysteine or histidine residues results in defective packaging of genomic viral RNA and formation of non-infectious particles, making these structures potentially attractive targets for antiviral therapy. We recently reported that aromatic C-nitroso ligands of poly(ADP-ribose) polymerase preferentially destabilize one of the two (Cys-X2-Cys-X28-His-X2-Cys) zinc-fingers with concomitant loss of enzymatic activity, coincidental with selective cytocidal action of the C-nitroso substituted ligands on cancer cells. Based on the occurrence of (3Cys, 1His) zinc-binding sites in both retroviral nucleocapsid and gag proteins and in poly(ADP-ribose) polymerase, we reasoned that the C-nitroso compounds may also have antiretroviral effects. We show here that two such compounds, 3-nitrosobenzamide and 6-nitroso-1,2-benzopyrone, inhibit infection of human immunodeficiency virus HIV-1 in human lymphocytes and also eject zinc from isoalted HIV-1 nucleocapsid zinc fingers and from intact HIV-1 virions. Thus the design of zinc-ejecting agents that target retroviral zinc fingers represents a new approach to the chemotherapy of AIDS.
所有已知逆转录病毒株的逆转录病毒核衣壳蛋白和gag前体蛋白都含有一或两个不变序列Cys-X2-Cys-X4-His-X4-Cys的拷贝，该序列在成熟病毒颗粒中与锌结合。半胱氨酸或组氨酸残基的修饰会导致基因组病毒RNA包装缺陷并形成无感染性的颗粒，使这些结构成为抗病毒治疗潜在的有吸引力的靶点。我们最近报道，聚（ADP-核糖）聚合酶的芳香族C-亚硝基配体优先使两个（Cys-X2-Cys-X28-His-X2-Cys）锌指中的一个不稳定，同时酶活性丧失，这与C-亚硝基取代配体对癌细胞的选择性杀细胞作用同时发生。基于逆转录病毒核衣壳蛋白和gag蛋白以及聚（ADP-核糖）聚合酶中（3个半胱氨酸，1个组氨酸）锌结合位点的存在，我们推测C-亚硝基化合物可能也具有抗逆转录病毒作用。我们在此表明，两种这样的化合物，3-亚硝基苯甲酰胺和6-亚硝基-1,2-苯并吡喃，可抑制人类免疫缺陷病毒HIV-1在人淋巴细胞中的感染，还能从分离的HIV-1核衣壳锌指和完整的HIV-1病毒体中逐出锌。因此，设计靶向逆转录病毒锌指的锌逐出剂代表了一种治疗艾滋病的新方法。
