New Phosphorus Analogs of Bevirimat: Synthesis, Evaluation of Anti-HIV-1 Activity and Molecular Docking Study
New Phosphorus Analogs of Bevirimat: Synthesis, Evaluation of Anti-HIV-1 Activity and Molecular Docking Study
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DOI：
10.3390/ijms20205209
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发表时间：
2019-10-02
影响因子：
5.6
通讯作者：
Boryczka, Stanislaw
中科院分区：
文献类型：
--
作者：
Chrobak, Elwira;Marciniec, Krzysztof;Boryczka, Stanislaw
自人类免疫缺陷病毒（HIV）流行开始以来，已经开发出许多具有不同作用机制的药物组，这些药物可以抑制HIV病毒血症。3-O-（3 '，3' -二甲基琥珀酰基）桦木酸（Betulinic acid，BVM）是第一个发现的HIV成熟抑制剂。在本工作中，3-羧基酰基桦木酸的磷酸酯和膦酸酯衍生物的合成和抗HIV-1活性的评价。体外研究表明，BVM的30-二乙基膦酸酯类似物（化合物14 a）具有与BVM相当的效果（半数最大抑制浓度（IC 50）分别等于0.02 μ M和0.03 μ M），并且也具有更高的选择性（选择性指数：分别为3450和967）。为探讨14 a抗病毒作用的可能机制，对HIV-1衣壳蛋白（CA）-间隔肽1（SP1）Gag蛋白C-末端结构域（CTD）进行分子对接，命名为CTD-SP1。与BVM和蛋白质之间的相互作用相比，观察到由膦酸酯基团产生的配体14 a和蛋白质之间的强相互作用的数量增加。
Since the beginning of the human immunodeficiency virus (HIV) epidemic, many groups of drugs characterized by diverse mechanisms of action have been developed, which can suppress HIV viremia. 3-O-(3',3' -Dimethylsuccinyl) betulinic acid, known as bevirimat (BVM), was the first compound in the class of HIV maturation inhibitors. In the present work, phosphate and phosphonate derivatives of 3-carboxyacylbetulinic acid were synthesized and evaluated for anti-HIV-1 activity. In vitro studies showed that 30-diethylphosphonate analog of BVM (compound 14a) has comparable effects to BVM (half maximal inhibitory concentrations (IC50) equal to 0.02 mu M and 0.03 mu M, respectively) and is also more selective (selectivity indices: 3450 and 967, respectively). To investigate the possible mechanism of antiviral effect of 14a, molecular docking was carried out on the C-terminal domain (CTD) of HIV-1 capsid (CA)-spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1, which was described as a molecular target for maturation inhibitors. Compared with interactions between BVM and the protein, an increased number of strong interactions between ligand 14a and protein, generated by the phosphonate group, was observed.