Structural and biochemical study on the inhibitory activity of derivatives of 5-nitro-furan-2-carboxylic acid for RNase H function of HIV-1 reverse transcriptase
Structural and biochemical study on the inhibitory activity of derivatives of 5-nitro-furan-2-carboxylic acid for RNase H function of HIV-1 reverse transcriptase
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DOI：
10.1016/j.bmc.2010.12.011
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发表时间：
2011-01-15
影响因子：
3.5
通讯作者：
Hoshino, Tyuji
中科院分区：
文献类型：
--
作者：
Yanagita, Hiroshi;Urano, Emiko;Hoshino, Tyuji
耐药变异的快速出现是HIV-1感染性疾病化疗中最严重的问题之一。作用于未被批准的药物处理的靶点的抑制剂对于抑制耐药病毒非常重要。HIV-1逆转录酶具有两种酶功能，即DNA聚合酶和RNase H活性。RNase H活性是一类新的抗病毒药物的有吸引力的靶标。在我们之前用20，000个小分子量化合物筛选中发现的热门化学品的基础上，我们合成了5-硝基-呋喃-2-羧酸的衍生物。在生物化学测定中测量RNase H酶活性的抑制，实时监测来自消化的RNA底物的荧光发射。几种衍生物显示出更高的抑制活性的命中化学品。5-硝基-呋喃-2-羧酸部分的调节导致抑制效力急剧下降。与此相反，许多衍生物与其他部分的调制保留不同程度的抑制活性。这些发现表明活性衍生物的结合模式，其中在硝基呋喃部分以直链形式排列的三个氧原子与位于RNase H反应位点的两个二价金属离子配位。因此，硝基呋喃羧酸部分是RNase H抑制的关键支架之一。值得注意的是，与原始命中化合物相比，衍生物的RNA酶H抑制效力提高了18倍，并且对于显示抑制活性的大多数衍生物没有观察到显著的细胞毒性。由于化合物在硝基呋喃部分相对的部分仍有很大的修饰空间，进一步的化学转化将导致化合物效力和特异性的改善。(C)2010爱思唯尔有限公司版权所有。
Rapid emergence of drug-resistant variants is one of the most serious problems in chemotherapy for HIV-1 infectious diseases. Inhibitors acting on a target not addressed by approved drugs are of great importance to suppress drug-resistant viruses. HIV-1 reverse transcriptase has two enzymatic functions, DNA polymerase and RNase H activities. The RNase H activity is an attractive target for a new class of antiviral drugs. On the basis of the hit chemicals found in our previous screening with 20,000 small molecular-weight compounds, we synthesized derivatives of 5-nitro-furan-2-carboxylic acid. Inhibition of RNase H enzymatic activity was measured in a biochemical assay with real-time monitoring of florescence emission from the digested RNA substrate. Several derivatives showed higher inhibitory activities that those of the hit chemicals. Modulation of the 5-nitro-furan-2-carboxylic moiety resulted in a drastic decrease in inhibitory potency. In contrast, many derivatives with modulation of other parts retained inhibitory activities to varying degrees. These findings suggest the binding mode of active derivatives, in which three oxygen atoms aligned in a straight form at the nitro-furan moiety are coordinated to two divalent metal ions located at RNase H reaction site. Hence, the nitro-furan-carboxylic moiety is one of the critical scaffolds for RNase H inhibition. Of note, the RNase H inhibitory potency of a derivative was improved by 18-fold compared with that of the original hit compound, and no significant cytotoxicity was observed for most of the derivatives showing inhibitory activity. Since there is still much room for modification of the compounds at the part opposite the nitro-furan moiety, further chemical conversion will lead to improvement of compound potency and specificity. (C) 2010 Elsevier Ltd. All rights reserved.