Structure-based identification of small molecule compounds targeting cell cyclophilin A with anti-HIV-1 activity
Structure-based identification of small molecule compounds targeting cell cyclophilin A with anti-HIV-1 activity
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DOI：
10.1016/j.ejphar.2007.03.023
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发表时间：
2007-06-22
影响因子：
5
通讯作者：
Yu, Long
中科院分区：
文献类型：
--
作者：
Chen, Shuai;Zhao, Xuemei;Yu, Long
亲环素A在许多细胞过程中扮演蛋白质折叠伴侣和细胞内转运的角色。以往的研究表明，亲环素A可以与HIV-1(人类免疫缺陷病毒1型)Gag蛋白相互作用，增强病毒的感染性。许多亲环素A抑制剂，如环孢菌素A，在体外可以抑制HIV-1的复制。在这里，我们报告了一种基于结构的新型非肽类亲环素A抑制剂作为抗HIV先导化合物的鉴定。在计算机辅助虚拟筛选和随后的表面等离子体共振(SPR)分析之后，选择了12个低分子亲环素A配体来进一步评价它们在体外对亲环素A的肽-脯氨基顺反异构酶(PPlase)活性和HIV-1复制的抑制作用。其中5个化合物(FD5、FD8、FD9、FD10和FD12)对PPlase活性和HIV-1感染均有抑制作用。这些活性化合物将作为结构与活性关系(SAR)和优化研究的先导，以设计更有效的抗HIV-1治疗药物，并作为研究亲环素对HIV-1复制的影响的探针。(C)2007 Elsevier B.V.保留所有权利。
Cyclophilin A acts as protein folding chaperones and intracellular transports in many cellular processes. Previous studies have shown that cyclophilin A can interact with HIV-1 (human immunodeficiency virus type 1) gag protein and enhance viral infectivity. Many cyclophilin A inhibitors such as cyclosporin A can inhibit HIV-1 replication in vitro. Here, we report a structure-based identification of novel non-peptidic cyclophilin A inhibitors as anti-HIV lead compounds. Following a computer-aided virtual screening and subsequent surface plasmon resonance (SPR) analysis, 12 low molecular weight cyclophilin A ligands were selected for further evaluation of their in vitro inhibition of peptidyl-prolyl cis-trans isomerase (PPlase) activity of cyclophilin A and HIV-1 replication. Five of these compounds (FD5, FD8, FD9, FD10 and FD12) exhibited inhibition against both PPlase activity and HIV-1 infection. These active compounds will be used as leads for structure and activity relationship (SAR) and optimization studies in order to design more effective anti-HIV-1 therapeutics, and as probes for investigating the effect of cyclophilins on HIV-1 replication. (c) 2007 Elsevier B.V. All rights reserved.