Synthesis and structure-activity relationship studies of HIV-1 virion infectivity factor (Vif) inhibitors that block viral replication.
Synthesis and structure-activity relationship studies of HIV-1 virion infectivity factor (Vif) inhibitors that block viral replication.
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DOI：
10.1002/cmdc.201200079
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发表时间：
2012-07
期刊：
影响因子：
3.4
通讯作者：
Rana, Tariq M.
中科院分区：
文献类型：
--
作者：
Ali, Akbar;Wang, Jinhua;Nathans, Robin S.;Cao, Hong;Sharova, Natalia;Stevenson, Mario;Rana, Tariq M.
关键词：
HIV-1 Vif蛋白对体内病毒复制至关重要，它可以保护病毒免受先天抗病毒细胞因子APOBEC3G(A3G)的攻击，是开发抗病毒治疗药物的一个有吸引力的靶点。在这里，我们评估了RN18的构效关系，RN18是一种小分子，最近被发现是Vif功能的抑制剂，通过抑制Vif-A3G的相互作用，仅在表达A3G的非许可细胞中阻止病毒复制。发展了微波辅助交叉偶联反应，合成了一系列苯环上具有不同键和取代的RN18类似物。一种基于双细胞的检测系统被用来评估在非许可(H9)和许可(MT-4)细胞中对野生型HIV-1的抗病毒活性，这也允许评估特异性。总体而言，苯基取代的变化对抗病毒效力和特异性是不利的，但酰胺和醚键的异构化取代相对耐受性较好。这些SAR数据定义了Vif特异性活性的结构要求，确定了具有更高抗病毒效力和特异性的新化合物，并为进一步探索开发新的抗病毒疗法提供了线索。
The HIV-1 Vif protein, essential for in vivo viral replication, protects the virus from innate antiviral cellular factor APOBEC3G (A3G), and is an attractive target for developing antiviral therapeutics. Here we have evaluated the structure-activity relationships of RN18, a small molecule recently identified as an inhibitor of Vif function that blocks viral replication only in non-permissive cells expressing A3G, by inhibiting Vif-A3G interactions. Microwave-assisted cross-coupling reactions were developed to prepare a series of RN18 analogues with diverse linkages and substitutions on the phenyl rings. A dual cell-based assay system was used to assess antiviral activity against wild-type HIV-1 in both non-permissive (H9) and permissive (MT-4) cells that also allowed evaluation of specificity. In general, variations of phenyl substitutions were detrimental for antiviral potency and specificity, but isosteric replacements of amide and ether linkages were relatively well tolerated. These SAR data define structural requirements for Vif-specific activity, identify new compounds with improved antiviral potency and specificity, and provide leads for further exploration to develop new antiviral therapeutics.
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影响因子：
46.9
作者：
Nathans, Robin;Cao, Hong;Sharova, Natalia;Ali, Akbar;Sharkey, Mark;Stranska, Ruzena;Stevenson, Mario;Rana, Tariq M.
通讯作者：
Rana, Tariq M.
影响因子：
16
作者：
Stopak, K;de Noronha, C;Greene, WC
通讯作者：
Greene, WC
影响因子：
64.8
作者：
Sheehy, AM;Gaddis, NC;Malim, MH
通讯作者：
Malim, MH
影响因子：
3.2
作者：
Ali, Akbar;Ghosh, Animesh;Rana, Tariq M.
通讯作者：
Rana, Tariq M.
影响因子：
5.2
作者：
Bates, CG;Gujadhur, RK;Venkataraman, D
通讯作者：
Venkataraman, D