Structure-based design, synthesis, and biological evaluation of novel inhibitors of human cyclophilin A
Structure-based design, synthesis, and biological evaluation of novel inhibitors of human cyclophilin A
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DOI：
10.1021/jm050716a
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发表时间：
2006-02-09
影响因子：
7.3
通讯作者：
Chavanieu, A
中科院分区：
文献类型：
--
作者：
Guichou, JF;Viaud, J;Chavanieu, A
亲环素A参与许多细胞过程，包括蛋白质折叠和细胞内转运。由于亲环素A已被证明与HIV-1 gag蛋白相互作用并增强病毒感染性，因此非免疫抑制性亲环素A配体可能代表一类新的抗HIV治疗剂。在这里，我们报告了一个虚拟的筛选使用结构和药效团为基础的设计，以确定原来的非肽亲环配体。在化合物1 [1-（3-苄氧基吡啶-2-基）-3-（3-氯苯基）脲]和2 [1-（3-苄氧基吡啶-2-基）-3-（3-三氟甲基苯基）脲]（IC 50 = 0.3 μ M）的先导鉴定之后，从二芳基脲支架合成了一系列分子，并评价它们抑制亲环素A的顺-反异构酶活性的体外能力。分子修饰提供了几种更有效的化合物，特别是类似物4d和4 i，IC 50分别为14和20 nM。然后，我们评估了类似物1和2对永生化细胞和原代细胞中HIV病毒粒子感染性的影响。在复制缺陷的一轮感染试验中，1和2都降低了病毒粒子的感染性，但只有1个削弱了人外周血单核细胞中的野生型HIV感染。
Cyclophilin A is involved in many cellular processes, including protein folding and intracellular transports. Because cyclophilin A has been shown to interact with HIV-1 gag proteins and to enhance the viral infectivity, nonimmunosuppressive cyclophilin A ligands may represent a new class of therapeutic agents against HIV. Here, we report a virtual screening using structure- and pharmacophore-based design to identify original nonpeptidic cyclophilin ligands. Following a lead identification of compounds 1 [1-(3-benzyloxypyridin-2-yl)-3-(3-chlorophenyl)urea] and 2 [1-(3-benzyloxypyridin-2-yl)-3-(3-trifluoromethylphenyl)urea] (IC50 = 0.3 mu M), a series of molecules were synthesized from a diarylurea scaffold and evaluated for their in vitro ability to inhibit the cis-trans isomerase activity of cyclophilin A. Molecular modifications provided several more potent compounds, in particular analogues 4d and 4i with IC50 of 14 and 20 nM, respectively. Then, we evaluated the effect of analogues 1 and 2 on HIV virion infectivity in both immortalized and primary cells. Both 1 and 2 reduced virion infectivity in the replication-defective one-round infection assay, but only 1 impaired wild-type HIV infection in human peripheral blood mononuclear cells.