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Review Article

利用多目标靶向对接设计新型HIV-IN系链双功能抑制剂

卷 26, 期 15, 2019

页: [2574 - 2600] 页: 27

弟呕挨: 10.2174/0929867325666180406114405

价格: $65

摘要

目前，使用的抗逆转录病毒HIV治疗药物专门针对病毒生命周期必需的酶中的关键组。其基因突变的增加改变了这些病毒酶，这些酶一旦发生突变就可以逃避治疗靶向，这种效应可以提供抗药性。为了避免这种情况，我们的研究解决了设计和衍生HIV-Integrase（HIV-IN）抑制剂的策略，该抑制剂同时靶向两个IN功能域，即使酶积累了许多突变也使其失活。首先，我们回顾IN的酶促作用，将复制的病毒DNA插入宿主T淋巴细胞的染色体中，突出其主要功能和结构特征，使其受到抑制作用。从功能和结构的角度来看，我们提出了所有类别的HIV-IN抑制剂及其最具代表性的候选者。对于每种选择的化合物，我们还解释了其抑制IN的机制。我们使用最近解析的冷冻EM IN四聚体来自DNA复合物，在其上我们对接各种参考IN抑制性化学支架，例如靶向相邻的功能性IN结构域。配对具有互补活性的化合物，它们停靠在IN结构微域的附近，我们设计了双功能新药，它们不仅对IN突变更具弹性，而且可能是比原始对应物更有效的抑制剂。在我们的综述结束时，我们提出了将这些配对化合物与增强的协同IN抑制作用联系起来的合成途径。

关键词: HIV，整合酶，RT，ART，LTR，NTD，CCD，CTD。

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