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基于结构鉴定具有抗HIV-1活性的靶向细胞亲环素A的小分子化合物

Structure-based identification of small molecule compounds targeting cell cyclophilin A with anti-HIV-1 activity.

作者信息

Chen Shuai, Zhao Xuemei, Tan Jinzhi, Lu Hong, Qi Zhi, Huang Qiang, Zeng Xianzhuo, Zhang Mingjun, Jiang Shibo, Jiang Hualiang, Yu Long

机构信息

State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, People's Republic of China.

出版信息

Eur J Pharmacol. 2007 Jun 22;565(1-3):54-9. doi: 10.1016/j.ejphar.2007.03.023. Epub 2007 Mar 24.

DOI:10.1016/j.ejphar.2007.03.023
PMID:17449029
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3033441/
Abstract

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 (PPIase) activity of cyclophilin A and HIV-1 replication. Five of these compounds (FD5, FD8, FD9, FD10 and FD12) exhibited inhibition against both PPIase 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.

摘要

亲环素A在许多细胞过程中充当蛋白质折叠伴侣和细胞内转运蛋白。先前的研究表明，亲环素A可与HIV-1（1型人类免疫缺陷病毒）gag蛋白相互作用并增强病毒感染性。许多亲环素A抑制剂，如环孢素A，可在体外抑制HIV-1复制。在此，我们报告基于结构鉴定新型非肽类亲环素A抑制剂作为抗HIV先导化合物。通过计算机辅助虚拟筛选和随后的表面等离子体共振（SPR）分析，选择了12种低分子量亲环素A配体，以进一步评估它们对亲环素A肽基脯氨酰顺反异构酶（PPIase）活性和HIV-1复制的体外抑制作用。其中5种化合物（FD5、FD8、FD9、FD10和FD12）对PPIase活性和HIV-1感染均表现出抑制作用。这些活性化合物将用作结构活性关系（SAR）和优化研究的先导物，以设计更有效的抗HIV-1治疗药物，并用作研究亲环素对HIV-1复制影响的探针。

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