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首页> 外文期刊>Biochemistry >INHIBITION OF THE HUMAN IMMUNODEFICIENCY VIRUS TYPE I INTEGRASE BY GUANOSINE QUARTET STRUCTURES
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INHIBITION OF THE HUMAN IMMUNODEFICIENCY VIRUS TYPE I INTEGRASE BY GUANOSINE QUARTET STRUCTURES

机译：花青素四倍体结构对人免疫缺陷病毒I型整合酶的抑制作用

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An oligonucleotide (T30177) composed entirely of deoxyguanosine and thymidine has previously been shown to fold upon itself in the presence of potassium into a highly stable four-stranded DNA structure containing two stacked deoxyguanosine quarters (G4s). T30177 also protects host cells from the cytopathic effects of human immunodeficiency virus type 1 (HIV-1). We report that this G4 oligonucleotide is the most potent inhibitor of HIV-1 integrase identified to date, with IC50 values in the nanomolar range. Both the number of quarters formed and the sequence of the loops between the quartets are important for optimal activity. T30177 binds to HIV-1 integrase without being processed and blocks the binding of the normal viral DNA substrate to the enzyme. The normal DNA substrate was not able to compete off T30177 binding to HIV-1 integrase, indicating a tight binding of G4s to the enzyme. Experiments with truncated HIV-1 integrases indicate that the N-terminal region containing a putative zinc finger is required for inhibition by T30177 and that T30177 binds better to full-length or deletion mutant integrases containing the zinc finger region than to a deletion mutant consisting of only the central catalytic domain. The N-terminal region of integrase alone is able to bind efficiently to T30177, but not the linear viral DNA substrate, in the presence of zinc. Hence, G4s represent the first class of compounds that inhibit HIV-1 integrase by interacting with the enzyme N-terminal domain, The greater inhibitory potency of T30177 in buffer containing magnesium versus manganese suggests that divalent metal ion coordination along the phosphodiester backbone may play a role in the inhibitory activity. T30177 inhibited HIV-2 integrase with similar potency as HIV-1 but inhibited feline and simian immunodeficiency virus integrases at higher concentrations, suggesting selectivity can be achieved. We propose that novel AIDS therapies could be based upon guanosine quartets as inhibitors of HIV-I integrase.
机译：先前已显示出，完全由脱氧鸟苷和胸苷组成的寡核苷酸（T30177）在钾存在下会自身折叠成高度稳定的四链DNA结构，该结构包含两个堆叠的脱氧鸟苷四分之一（G4s）。 T30177还保护宿主细胞免受1型人类免疫缺陷病毒（HIV-1）的细胞病变作用。我们报告说，此G4寡核苷酸是迄今为止确定的最有效的HIV-1整合酶抑制剂，IC50值在纳摩尔范围内。四重奏之间形成的四分之一数量和循环顺序对于最佳活动都很重要。 T30177无需加工即可与HIV-1整合酶结合，并阻断正常病毒DNA底物与酶的结合。正常的DNA底物无法与T30177结合到HIV-1整合酶竞争，表明G4s与酶紧密结合。截短的HIV-1整合物的实验表明，含有推定的锌指的N端区域是T30177抑制所必需的，并且T30177与含有锌指区域的全长或缺失突变体整合体的结合要比由以下组成的缺失突变体更好地结合：仅中央催化域。在锌的存在下，仅整合酶的N末端区域能够有效结合T30177，但不能结合线性病毒DNA底物。因此，G4代表通过与酶的N末端结构域相互作用而抑制HIV-1整合的第一类化合物。T30177在含镁和锰的缓冲液中具有更大的抑制能力，表明沿磷酸二酯主链的二价金属离子配位可能起到在抑制活性中的作用。 T30177抑制HIV-2整合的能力与HIV-1相似，但以更高的浓度抑制猫和猿猴免疫缺陷病毒的整合，表明可以实现选择性。我们提出新的艾滋病疗法可以基于鸟嘌呤四联体作为HIV-1整合酶的抑制剂。

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