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首页> 外文期刊>Medicinal chemistry >Inhibition of HIV-1 ribonuclease H activity by novel frangula-emodine derivatives.
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Inhibition of HIV-1 ribonuclease H activity by novel frangula-emodine derivatives.

机译：新型的鸡蛋花-甜菜碱衍生物对HIV-1核糖核酸酶H的抑制作用。

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摘要

The HIV-1 reverse transcriptase (RT) associated ribonuclease H (RNase H) activity hydrolyzes the RNA component of the viral heteroduplex RNA:DNA replication intermediate. Even though this function is essential for viral replication, until now only very few compounds have been reported to inhibit it. Anthraquinones are common secondary metabolites which have diverse biological activities. In particular, some of them have been reported to inhibit the HIV-1 RT polymerase and integrase activities in biochemical assays. Given the structural similarities between integrase and RNase H proteins, we synthesized a series of frangula-emodine derivatives and showed that the introduction of a bromine atom in position 7 of the anthraquinone structure leads to derivatives which are able to inhibit both HIV-1 polymerase and RNase H functions at micromolar concentrations. Mechanism of action studies performed on the 7-brom-6-capital O, Cyrillic-phenacyl-1,8-dihydroxy-3-methyl anthraquinone (K67) showed that this compound is a non-competitive inhibitor of the RNase H function and that it binds to a site which is not overlapping to the non-nucleoside RT inhibitors binding site. This study demonstrates that anthraquinone derivatives may be a scaffold to be further developed to obtain selective HIV-1 RNase H inhibitors and represent a new step toward the identification of new anti-RT agents.
机译：与HIV-1逆转录酶（RT）相关的核糖核酸酶H（RNase H）活性可水解病毒异源双链RNA：DNA复制中间体的RNA成分。尽管此功能对于病毒复制至关重要，但迄今为止，只有极少数化合物可抑制该功能。蒽醌是常见的次级代谢产物，具有多种生物学活性。特别是，据报道其中一些在生化分析中抑制HIV-1 RT聚合酶和整合酶活性。考虑到整合酶和RNase H蛋白之间的结构相似性，我们合成了一系列的鸡蛋花-甜菜碱衍生物，结果表明在蒽醌结构7位引入溴原子会导致衍生物同时抑制HIV-1聚合酶和RNase H在微摩尔浓度下起作用。对7-brom-6-资本O，西里尔-苯甲酰基-1,8-二羟基-3-甲基蒽醌（K67）进行的作用机理研究表明，该化合物是RNase H功能的非竞争性抑制剂，它与不与非核苷RT抑制剂结合位点不重叠的位点结合。这项研究表明，蒽醌衍生物可能是一种支架，需要进一步开发以获得选择性的HIV-1 RNase H抑制剂，并代表了鉴定新的抗RT药物的新步骤。

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