The management of Human Immunodeficiency Virus type 1 (HIV-1) infection requires life-long treatment that is associated with chronic toxicity and possible selection of drug-resistant strains. A new opportunity for drug intervention is offered by antivirals that act as allosteric inhibitors targeting two viral functions (dual inhibitors). In this work, we investigated the effects of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) derivatives on both HIV-1 Integrase (IN) and Reverse Transcriptase associated Ribonuclease H (RNase H) activities. Among the tested compounds, the dihydroxyindole-carboxamide 5 was able to inhibit in the low micromolar range (1-18 μM) multiple functions of IN, including functional IN-IN interactions, IN-LEDGF/p75 binding and IN catalytic activity. Docking and site-directed mutagenesis studies have suggested that compound 5 binds to a previously described HIV-1 IN allosteric pocket. These observations indicate that 5 is structurally and mechanistically distinct from the published allosteric HIV-1 IN inhibitors. Moreover, compound 5 also inhibited HIV-1 RNase H function, classifying this molecule as a dual HIV-1 IN and RNase H inhibitor able to impair the HIV-1 virus replication in cell culture. Overall, we identified a new scaffold as a suitable platform for the development of novel dual HIV-1 inhibitors.

中文翻译：

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发现二羟基吲哚-2-羧酸衍生物为双变构HIV-1整合酶和逆转录酶相关的核糖核酸酶H抑制剂。

处理人类免疫缺陷病毒1型（HIV-1）感染需要终生治疗，这种治疗与慢性毒性和可能选择的耐药菌株有关。抗病毒药物为靶向两种病毒功能的变构抑制剂（双重抑制剂）提供了新的药物干预机会。在这项工作中，我们调查了5，6-二羟基吲哚-2-羧酸（DHICA）衍生物对HIV-1整合酶（IN）和逆转录酶相关的核糖核酸酶H（RNase H）活性的影响。在测试的化合物中，二羟基吲哚-羧酰胺5能够在低微摩尔范围（1-18μM）内抑制IN的多种功能，包括功能性IN-IN相互作用，IN-LEDGF / p75结合和IN催化活性。对接和定点诱变研究表明，化合物5与先前描述的HIV-1 IN变构口袋结合。这些观察结果表明5在结构和机械上与已公开的变构HIV-1 IN抑制剂不同。此外，化合物5还抑制HIV-1 RNase H的功能，将该分子归为能够破坏细胞培养物中HIV-1病毒复制的双重HIV-1 IN和RNase H抑制剂。总体而言，我们确定了一种新的支架，作为开发新型双重HIV-1抑制剂的合适平台。将该分子分类为能够破坏细胞培养物中HIV-1病毒复制的双重HIV-1 IN和RNase H抑制剂。总体而言，我们确定了一种新的支架，作为开发新型双重HIV-1抑制剂的合适平台。将该分子分类为能够破坏细胞培养物中HIV-1病毒复制的双重HIV-1 IN和RNase H抑制剂。总体而言，我们确定了一种新的支架，作为开发新型双重HIV-1抑制剂的合适平台。