Activity of different bicyclam derivatives against human immunodeficiency virus depends on their interaction with the CXCR4 chemokine receptor
Activity of different bicyclam derivatives against human immunodeficiency virus depends on their interaction with the CXCR4 chemokine receptor
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DOI：
10.1124/mol.55.1.67
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发表时间：
1999-01-01
影响因子：
3.6
通讯作者：
Schols, D
中科院分区：
文献类型：
--
作者：
Esté, JA;Cabrera, C;Schols, D
双环胺是一类新型的选择性抗HIV抑制剂，对HIV的T细胞嗜性株具有强效活性。原型化合物bicyclam AMD 3100对不同的HIV-I毒株（包括临床分离株）的EC 50为1至10 ng/ml。AMD 3100显示与CXC趋化因子受体CXCR 4相互作用，CXCR 4是HIV嗜T细胞株使用的主要辅助受体。在这里，我们描述了不同的bicyclam衍生物与CXCR 4的相互作用。双环类药物的抗HIV效力与其抑制抗CXCR 4单克隆抗体结合或抑制由基质细胞衍生因子-1 α（CXCR 4的天然配体）诱导的细胞内Ca++信号的能力之间存在密切相关性（r（2）= 0.7）。这些结果表明双环类的作用机制主要是通过它们与CXCR 4的相互作用介导的。与CXCR 4的最有效的相互作用以及因此抗HIV活性由双环胺类似物显示，所述双环胺类似物具有由芳香族（苯基）桥连接的十四个成员组成的环胺环。阐明受体相互作用的结构要求和双环胺与CXCR 4相互作用的位点将有助于理解HIV-细胞融合。
Bicyclams represent a novel class of selective anti-HIV inhibitors with potent activity against T-cell tropic strains of HIV. The prototype compound, the bicyclam AMD3100, has an EC50 of I to 10 ng/ml against different strains of HIV-I, including clinical isolates. AMD3100 was shown to interact with the CXC-chemokine receptor CXCR4, the main coreceptor used by T-cell tropic strains of HIV. Here we describe the interaction of different bicyclam derivatives with CXCR4. A close correlation (r(2) = 0.7) was found between the anti-HIV potency of the bicyclams and their ability to inhibit the binding of an anti-CXCR4 monoclonal antibody or the intracellular Ca++ signal induced by the stromal cell-derived factor-1 alpha, the natural ligand of CXCR4. These results indicate that the mechanism of action of bicyclams is primarily mediated by their interaction with CXCR4. The most potent interaction with CXCR4 and thus anti-HIV activity was shown by bicyclam analogs with cyclam rings composed of fourteen members that are linked by an aromatic (phenyl) bridge. Elucidating the structural requirements for receptor interaction and the site(s) of interaction of bicyclams with CXCR4 will aid in the understanding of HIV-cell fusion.