Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF/p75
Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF/p75
复制标题
设计和发现基于类黄酮的 HIV-1 整合酶抑制剂，靶向活性位点并与 LEDGF/p75 相互作用
DOI：
10.1016/j.bmc.2014.04.016
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发表时间：
2014-06-15
影响因子：
3.5
通讯作者：
Long, Ya-Qiu
中科院分区：
文献类型：
--
作者：
Li, Bo-Wen;Zhang, Feng-Hua;Long, Ya-Qiu
HIV整合酶（integrase，IN）是病毒复制所必需的酶。目前，三种IN抑制剂已被批准用于治疗HIV-1感染。这三种药物都通过螯合酶活性部位的二价金属离子来选择性地抑制链转移反应。香料是一类具有多种生物活性的天然产物。它们的β-酮烯醇或邻苯二酚结构可以作为金属螯合基序，并可用于设计新的IN抑制剂。利用金属螯合作用作为药效团，我们在黄酮醇核心中引入适当的疏水基团，设计了基于天然产物的新型IN抑制剂。我们开发了选择性和有效的合成，以产生一系列单3/5/7/3 '/4'取代的黄酮衍生物。这些新化合物中的大多数在基于酶的测定中显示出优异的HIV-1 IN抑制活性，并且在基于细胞的测定中保护免受HIV-1感染。7-吗啉取代的7 c显示出有效的抗病毒活性（EC_（50）= 0.826 μ g/mL）和高的治疗指数（TI > 242）。更重要的是，这些羟基黄酮阻断IN-LEDGF/p75相互作用，具有低至亚微摩尔的IC 50值，并代表了一种新的支架，用于设计同时靶向催化位点以及蛋白质-蛋白质相互作用结构域的新一代药物。(C)2014爱思唯尔有限公司版权所有。
HIV integrase (IN) is an essential enzyme for the viral replication. Currently, three IN inhibitors have been approved for treating HIV-1 infection. All three drugs selectively inhibit the strand transfer reaction by chelating a divalent metal ion in the enzyme active site. Flavonoids are a well-known class of natural products endowed with versatile biological activities. Their beta-ketoenol or catechol structures can serve as a metal chelation motif and be exploited for the design of novel IN inhibitors. Using the metal chelation as a common pharmacophore, we introduced appropriate hydrophobic moieties into the flavonol core to design natural product-based novel IN inhibitors. We developed selective and efficient syntheses to generate a series of mono 3/5/7/3'/4'-substituted flavonoid derivatives. Most of these new compounds showed excellent HIV-1 IN inhibitory activity in enzyme-based assays and protected against HIV-1 infection in cell-based assays. The 7-morpholino substituted 7c showed effective antiviral activity (EC50 = 0.826 mu g/mL) and high therapeutic index (TI > 242). More significantly, these hydroxyflavones block the IN-LEDGF/p75 interaction with low-to sub-micromolar IC50 values and represent a novel scaffold to design new generation of drugs simultaneously targeting the catalytic site as well as protein-protein interaction domains. (C) 2014 Elsevier Ltd. All rights reserved.