Inhibition of HIV infection by CXCR4 and CCR5 chemokine receptor antagonists.
Inhibition of HIV infection by CXCR4 and CCR5 chemokine receptor antagonists.
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CXCR4 和 CCR5 趋化因子受体拮抗剂抑制 HIV 感染。
DOI：
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发表时间：
2001
影响因子：
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通讯作者：
D. Schols
中科院分区：
文献类型：
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作者：
E. Clercq;D. Schols
趋化因子受体CXCR 4和CCR 5分别被嗜T细胞（X4）和嗜巨噬细胞（R5）HIV-1株用作共受体，以进入其宿主细胞。CXCR 4、CXC趋化因子SDF-1和CCR 5、CC趋化因子RANTES、MIP-1 α和MIP-1 β的天然配体可抑制病毒进入。几种肽化合物，T22（18聚体）、T134（14聚体）、ALX 40 -4C（9聚体）和CGP 64222（也是9聚体），已被鉴定为CXCR 4拮抗剂并显示抗HIV活性。此外，HIV-1达特蛋白已被描述为具有抗HIV-1活性的“天然”CXCR 4拮抗剂。最有效和特异性的CXCR 4拮抗剂是双环类衍生物，其也有效地阻断X4 HIV复制。AMD 3100已被证明是一种高度特异性的CXCR 4拮抗剂，可持续阻断所有X4 HIV和双嗜性（R5/X4）变体的生长，这些变体使用CXCR 4进入细胞（细胞系、CXCR 4转染细胞系、淋巴细胞或单核细胞/巨噬细胞）。从双环胺类似物中，AMD 3100被选为临床候选药物，在初步I期（安全性）研究后，已进入II期（疗效）试验。第一种与CCR 5相互作用而不与CXCR 4相互作用的非肽化合物是一种季铵衍生物，称为TAK-779，它也具有有效但可变的抗HIV活性。我们相信，HIV进入/融合抑制剂将成为重要的新的抗病毒药物，以打击艾滋病。然而，与目前临床批准的药物一样，它们需要与靶向HIV复制周期其他方面的抗病毒药物（如逆转录酶和蛋白酶）组合使用，以获得最佳治疗效果。
The chemokine receptors CXCR4 and CCR5 are used as co-receptors by the T cell-tropic (X4) and macrophage-tropic (R5) HIV-1 strains, respectively, for entering their host cells. Viral entry can be inhibited by the natural ligands for CXCR4, the CXC chemokine SDF-1 and CCR5, the CC chemokines RANTES, MIP-1alpha and MIP-1beta. Several peptidic compounds, T22 (an 18-mer), T134 (a 14-mer), ALX40-4C (a 9-mer) and CGP 64222 (also a 9-mer), have been identified as CXCR4 antagonists and show anti-HIV activity. Also, the HIV-1 tat protein has been described as a 'natural' CXCR4 antagonist with anti-HIV-1 activity. The most potent and specific CXCR4 antagonists are the bicyclam derivatives, which also potently block X4 HIV replication. AMD3100 has proved to be a highly specific CXCR4 antagonist, which consistently blocks the outgrowth of all X4 HIV and dual-tropic (R5/X4) variants that use CXCR4 for entering the cells (cell lines, CXCR4-transfected cell lines, lymphocytes or monocytes/ macrophages). From the bicyclam analogues, AMD3100 was selected as the clinical drug candidate, which, after initial Phase I (safety) studies, has proceeded to Phase II (efficacy) trials. The first non-peptidic compound that interacts with CCR5, and not with CXCR4, is a quaternary ammonium derivative, called TAK-779, which also has potent but variable anti-HIV activity. We believe that HIV entry/fusion inhibitors will become important new antiviral agents to combat AIDS. However, like the current clinically approved agents, they will need to be used in combinations consisting of antivirals that target other aspects of the HIV replication cycle, such as reverse transcriptase and protease, to obtain optimum therapeutic effects.