Structure-activity of tetrad-forming oligonucleotides as a potent anti-HIV therapeutic drug
Structure-activity of tetrad-forming oligonucleotides as a potent anti-HIV therapeutic drug
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DOI：
10.1074/jbc.273.52.34992
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发表时间：
1998-12-25
影响因子：
4.8
通讯作者：
Hogan, ME
中科院分区：
文献类型：
--
作者：
Jing, NJ;Hogan, ME
最近，我们描述了仅含有 G 和 T 碱基的寡核苷酸（即 T30695 和 T30177）的设计和表征，它们是人类免疫缺陷病毒 1 型 (HIV-1) 在培养物中复制的有效抑制剂（Jing, N,, Rando, R, F,, Pommier, Y, 和 Hogan, M, E, (1997) Biochemistry 36, 12498-12505)，为了理解这一观察结果并合理化这些化合物寡核苷酸折叠的普遍高热稳定性，我们使用 NMR 方法，结合分子建模，获得 T30695 的高分辨率结构模型，T30695 是迄今为止已鉴定的最有效的整合酶抑制剂。在 Li+ 离子存在下获得的建模和 NMR 数据表明，T30695 呈现出具有扭曲的 G 八位组核心和一组三个开放、部分无序环的分子内折叠。这被称为Li+-型结构。基于 NMR 的模型表明，在与三个 K+ 等价物协调时，中心 G 八位组变得更加规则，并且环域变得有序和紧凑。这被称为K+型结构。基于对HIV-1整合酶的抑制测定，T30695表现出K+型结构对HIV-1整合酶活性的强烈抑制作用，但Li+型结构对HIV-1整合酶活性的抑制作用较差。结构/活性分析表明，K+诱导的四分体形成寡核苷酸（例如T30695和T30177）的构象转变在抑制HIV-1整合酶活性中发挥关键作用。
Recently, we have described the design and characterization of oligonucleotides containing only G and T bases, i.e. T30695 and T30177, that are potent inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in culture (Jing, N,, Rando, R, F,, Pommier, Y,, and Hogan, M, E, (1997) Biochemistry 36, 12498-12505), To understand that observation and to rationalize the generally high thermal stability of oligonucleotide folding for these compounds, we have used NMR methods, coupled to molecular modeling, to obtain a high resolution structure model for T30695, which is the most potent of the integrase inhibitors that have been identified thus far. Modeling and NMR data obtained in the presence of Li+ ions show that T30695 assumes an intramolecular fold with a distorted G-octet core and a set of three open, partially disordered loops. This is referred to as Li+-form structure. The NMR-based model suggests that, upon coordination with three K+ equivalents, the central G-octet becomes more regular and that the loop domains become orderly and compact. This is referred to as K+-form structure. Based upon the assay of inhibition of HIV-1 integrase, T30695 demonstrated a strong inhibition of HIV-1 integrase activity as the K+-form structure, but a poor inhibition of HIV-1 integrase activity as the Li+-form structure. The structure/activity analysis suggests that the K+-induced conformation transition of the tetrad-forming oligonucleotides, such as T30695 and T30177, plays a key role in inhibition of HIV-1 integrase activity.