DNA aptamers derived from HIV-1 RNase H inhibitors are strong anti-integrase agents
DNA aptamers derived from HIV-1 RNase H inhibitors are strong anti-integrase agents
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DOI：
10.1016/s0022-2836(02)01064-1
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发表时间：
2002-11-22
影响因子：
5.6
通讯作者：
Andréola, ML
中科院分区：
文献类型：
--
作者：
de Soultrait, VR;Lozach, PY;Andréola, ML
HIV-1整合酶是一种逆转录病毒编码酶，参与逆转录病毒基因组整合到宿主核DNA中，是一个有吸引力且尚未开发的靶点。迄今为止，具有潜在治疗价值的这种酶的抑制剂很少被描述。在寻找新的 HIV-1 靶标的过程中，我们最近描述了 DNA 寡脱氧核苷酸适体（ODN 93 和 ODN 112），它们是与 HIV-1 逆转录酶相关的 RNase H 活性的强抑制剂。 RNase H 和整合酶之间惊人的结构同源性促使我们研究 RNase H 抑制剂对整合酶的影响。源自 ODN 93 和 112（ODN 93del 和 112del）的较短 DNA 适体能够在纳摩尔范围内抑制 HIV-1 整合酶。它们具有富含 G 的序列，能够形成因 K+ 的存在而稳定的 G 四联体。这些离子的存在极大地提高了这些药物的抑制效率。在使用重组整合酶的无细胞测定系统中观察到 ODN 93del 和 ODN 112del 对酶活性的抑制，并且 HIV-1 复制在受感染的人类细胞中被消除。此外，细胞融合测定表明，这些药物在病毒复制停止的浓度下不会阻止病毒进入细胞。 (C) 2002 Elsevier Science Ltd. 保留所有权利。
HIV-1 integrase, the retroviral-encoded enzyme involved in the integration of the retrotranscribed viral genome into the host nuclear DNA is an attractive and still unexploited target. To date, very few inhibitors of this enzyme with a potential therapeutic value have been described. During the search for new HIV-1 targets, we recently described DNA oligodeoxynucleotide aptamers (ODN 93 and ODN 112) that are strong inhibitors of the RNase H activity associated with HIV-1 reverse transcriptase. The striking structural homology between RNase H and integrase led us to study the effect of the RNase H inhibitors on the integrase. Shorter DNA aptamers derived from ODNs 93 and 112 (ODNs 93del and 112del) were able to inhibit HIV-1 integrase in the nanomolar range. They had G-rich sequences able to form G-quartets stabilized by the presence of K+. The presence of these ions increased the inhibitory efficiency of these agents dramatically. Inhibition of enzymatic activities by ODN 93del and ODN 112del was observed in a cell-free assay system using a recombinant integrase and HIV-1 replication was abolished in infected human cells. Moreover, cell fusion assays showed that these agents do not block viral cell entry at concentrations where viral replication is stopped. (C) 2002 Elsevier Science Ltd. All rights reserved.