Lomonosov Moscow State University, Chemistry Department and Belozersky Institute of Physical and Chemical Biology, Moscow, Russia.
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
Eur J Med Chem. 2014 Feb 12;73:73-82. doi: 10.1016/j.ejmech.2013.11.028. Epub 2013 Dec 12.
The integration of viral DNA into the cell genome is one of the key steps in the replication cycle of human immunodeficiency virus type 1 (HIV-1). Therefore, the viral enzyme integrase (IN) catalyzing this process is of great interest as a target for new antiviral agents. We performed a structural-functional analysis of five different series of methylenebisphosphonates (BPs), PO3H2-C(R)(X)-PO3H2, as IN inhibitors with the goal of assessing structural elements required for the inhibitory activity. We found that IN is inhibited only by BP bearing a chlorobenzyl substituent R at the bridging carbon of the P-C-P backbone. These BP inhibited both IN-catalyzed reactions with similar efficacies. They were also active toward some INs with mutations characteristic for HIV-1 strains resistant to strand transfer inhibitors. The study of the mechanism of the IN inhibition by various BP showed that it is effected by the nature of the second substituent (X) at the bridging carbon. Among the tested compounds, only the BP with the amino group bound directly to the BP bridging carbon was found to be a noncompetitive inhibitor and, hence, it can be promising for further studies as potential inhibitor of the IN activity within the preintegration complex.
病毒 DNA 整合到细胞基因组中是人类免疫缺陷病毒 1 型 (HIV-1) 复制周期的关键步骤之一。因此，催化这一过程的病毒酶整合酶 (IN) 作为新抗病毒药物的靶点引起了极大的关注。我们对五种不同系列的亚甲基膦酸酯 (BP)，PO3H2-C(R)(X)-PO3H2，进行了结构-功能分析，作为 IN 抑制剂，旨在评估抑制活性所需的结构元件。我们发现只有在 P-C-P 主链的桥接碳原子上带有氯苄基取代基 R 的 BP 才能抑制 IN。这些 BP 以相似的效率抑制 IN 催化的两种反应。它们对一些具有对链转移抑制剂耐药特征的 HIV-1 株的 IN 突变也具有活性。对各种 BP 抑制 IN 机制的研究表明，它受桥接碳原子上第二个取代基 (X) 的性质影响。在所测试的化合物中，只有与 BP 桥接碳原子直接结合的氨基取代的 BP 被发现是非竞争性抑制剂，因此，它有望作为潜在的整合前复合物中 IN 活性抑制剂进行进一步研究。
