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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-RIVI activity
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A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-RIVI activity

机译：一种小分子，非肽类CCR5拮抗剂，具有高效且选择性的抗RIVI活性

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摘要

The beta-chemokine receptor CCRS is considered to be an attractive target for inhibition of macrophagetropic (CCRS-using or RS) HIV-I replication because individuals having a nonfunctional receptor (a homozygous 32-bp deletion in the CCRS coding region) are apparently normal but resistant to infection with RS HIV-1. In this study, we found that TAK-779, a nonpeptide compound with a small molecular weight (Mr 531.13), antagonized the binding of RANTES (regulated on activation, normal T cell expressed and secreted) to CCRS-expressing Chinese hamster ovary cells and blocked CCRS-mediated Ca2+ signaling at nanomoIar concentrations. The inhibition of beta-chemokine receptors by TAK-779 appeared to be specific to CCRS 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 RS HIV-1 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 1.63.7 nM in peripheral blood mononuclear cells, though it was totally inactive against T-cell line-tropic (CXCR4-using or X4) HIV-1.
机译：β趋化因子受体CCRS被认为是抑制巨噬细胞（使用CCRS或RS）HIV-1复制的诱人靶标，因为具有非功能受体（在CCRS编码区纯合32 bp缺失）的个体显然是正常的但可抵抗RS HIV-1感染。在这项研究中，我们发现TAK-779是一种分子量较小的非肽化合物（Mr 531.13），可拮抗RANTES（受激活，正常T细胞表达和分泌的调节）与表达CCRS的中国仓鼠卵巢细胞和在纳米浓度下阻断了CCRS介导的Ca2 +信号传导。 TAK-779对β-趋化因子受体的抑制作用似乎对CCRS具有特异性，因为该化合物在较小程度上拮抗CCR2b，但不影响CCR1，CCR3或CCR4。因此，TAK-779显示出对RS HIV-1复制的强效和选择性抑制，而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1.63.7 nM的浓度抑制了R5 HIV-1临床分离株和实验室菌株的复制，尽管它对T细胞系是完全无活性的（使用CXCR4或X4 ）HIV-1。

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