Discovery of dual inhibitors targeting both HIV-1 capsid and human cyclophilin A to inhibit the assembly and uncoating of the viral capsid
Discovery of dual inhibitors targeting both HIV-1 capsid and human cyclophilin A to inhibit the assembly and uncoating of the viral capsid
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DOI：
10.1016/j.bmc.2009.02.051
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发表时间：
2009-04-15
影响因子：
3.5
通讯作者：
Yang, Ming
中科院分区：
文献类型：
--
作者：
Li, Jiebo;Tan, Zhiwu;Yang, Ming
HIV-1的组装和拆卸（脱衣）过程对HIV-1的复制至关重要。HIV-1衣壳（CA）和人亲环蛋白A （CypA）在这些过程中起重要作用。我们设计并合成了一系列硫脲类化合物作为HIV-1组装和拆卸双重抑制剂，同时靶向HIV-1 CA蛋白和人CypA。siv诱导合胞体抗病毒评价表明，所有抑制剂在siv感染的CEM细胞浓度为0.6-15.8 μ M时均显示抗病毒活性，最大有效率为50%。通过紫外光谱分析、荧光结合亲和力和PPIase抑制实验，确定了它们对CA和CypA的结合能力。体外组装研究表明，这些化合物可以以剂量依赖的方式有效地破坏CA组装。所有这些分子都能以51.0-512.8 μ M的亲和力（Kd值）结合CypA，其中15个CypA结合化合物显示出有效的PPIase抑制活性（IC50值< 1 μ M），而在酶检测中它们既不能结合HIV-1蛋白酶也不能结合HIV-1整合酶。这些结果表明，15种化合物可以通过抑制CypA的PPIase活性来干扰衣壳分解和破坏CA组装，从而阻断HIV-1的复制。2009爱思唯尔有限公司版权所有。
HIV-1 assembly and disassembly (uncoating) processes are critical for the HIV-1 replication. HIV-1 capsid (CA) and human cyclophilin A (CypA) play essential roles in these processes. We designed and synthesized a series of thiourea compounds as HIV-1 assembly and disassembly dual inhibitors targeting both HIV-1 CA protein and human CypA. The SIV-induced syncytium antiviral evaluation indicated that all of the inhibitors displayed antiviral activities in SIV-infected CEM cells at the concentration of 0.6-15.8 mu M for 50% of maximum effective rate. Their abilities to bind CA and CypA were determined by ultraviolet spectroscopic analysis, fluorescence binding affinity and PPIase inhibition assay. Assembly studies in vitro demonstrated that the compounds could potently disrupt CA assembly with a dose-dependent manner. All of these molecules could bind CypA with binding affinities (Kd values) of 51.0-512.8 mu M. Fifteen of the CypA binding compounds showed potent PPIase inhibitory activities (IC50 values < 1 mu M) while they could not bind either to HIV-1 Protease or to HIV-1 Integrase in the enzyme assays. These results suggested that 15 compounds could block HIV-1 replication by inhibiting the PPIase activity of CypA to interfere with capsid disassembly and disrupting CA assembly. (C) 2009 Elsevier Ltd. All rights reserved.