A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity
A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity
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DOI：
10.1073/pnas.96.10.5698
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发表时间：
1999-05-11
影响因子：
11.1
通讯作者：
Fujino, M
中科院分区：
文献类型：
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作者：
Baba, M;Nishimura, O;Fujino, M
β-趋化因子受体CCR 5被认为是抑制嗜巨噬细胞（使用CCR 5或R5）HIV-1复制的有吸引力的靶标，因为具有非功能性受体（CCR 5编码区纯合32 bp缺失）的个体表面上正常，但对R5 HIV-1感染具有抗性。在本研究中，我们发现TAK-779（一种小分子量的非肽化合物（M-r 531.13））在纳摩尔浓度下拮抗RANTES（受活化调节，正常T细胞表达和分泌）与表达CCR 5的中国仓鼠卵巢细胞的结合，并阻断CCR 5介导的Ca 2+信号传导。TAK-779对β-趋化因子受体的抑制似乎对CCR 5具有特异性，因为该化合物拮抗CCR 2b的程度较低，但不影响CCR 1、CCR 3或CCR 4。因此，TAK-779对R5 HIV-I复制表现出高度强效和选择性抑制作用，对宿主细胞无任何细胞毒性。该化合物在外周血单核细胞中以1.6-3.7 nM的浓度抑制R5 HIV-1临床分离株以及实验室菌株的复制，但对嗜T细胞系（使用CXCR 4或X4）HIV-1完全无活性。
The beta-chemokine receptor CCR5 is considered to be an attractive target for inhibition of macrophage-tropic (CCR5-using or R5) HIV-1 replication because individuals having a nonfunctional receptor (a homozygous 32-bp deletion in the CCR5 coding region) are apparently normal but resistant to infection with R5 HIV-1. In this study, we found that TAK-779, a nonpeptide compound with a small molecular weight (M-r 531.13), antagonized the binding of RANTES (regulated on activation, normal T cell expressed and secreted) to CCR5-expressing Chinese hamster ovary cells and blocked CCR5-mediated Ca2+ signaling at nanomolar concentrations. The inhibition of beta-chemokine receptors by TAK-779 appeared to be specific to CCR5 because the compound antagonized CCR2b to a lesser extent but did not affect CCR1, CCR3, or CCR4. Consequently, TAK-779 displayed highly potent and selective inhibition of R5 HIV-I replication without showing any cytotoxicity to the host cells. The compound inhibited the replication of R5 HIV-1 clinical isolates as well as a laboratory strain at a concentration of 1.6-3.7 nM in peripheral blood mononuclear cells, though it was totally inactive against T-cell line-tropic (CXCR4-using or X4) HIV-1.