Baba M, Nishimura O, Kanzaki N, Okamoto M, Sawada H, Iizawa Y, Shiraishi M, Aramaki Y, Okonogi K, Ogawa Y, Meguro K, Fujino M
Division of Human Retroviruses, Center for Chronic Viral Diseases, Faculty of Medicine, Kagoshima University, Kagoshima 890-8520, Japan.
Proc Natl Acad Sci U S A. 1999 May 11;96(10):5698-703. doi: 10.1073/pnas.96.10.5698.
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 (Mr 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-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 1.6-3.7 nM in peripheral blood mononuclear cells, though it was totally inactive against T-cell line-tropic (CXCR4-using or X4) HIV-1.
β趋化因子受体CCR5被认为是抑制巨噬细胞嗜性（利用CCR5或R5）HIV-1复制的一个有吸引力的靶点，因为具有无功能受体（CCR5编码区纯合32bp缺失）的个体显然正常，但对R5 HIV-1感染具有抗性。在本研究中，我们发现TAK-779，一种分子量小（Mr 531.13）的非肽化合物，可拮抗RANTES（受激活调节、正常T细胞表达和分泌）与表达CCR5的中国仓鼠卵巢细胞的结合，并在纳摩尔浓度下阻断CCR5介导的Ca2+信号传导。TAK-779对β趋化因子受体的抑制似乎对CCR5具有特异性，因为该化合物对CCR2b的拮抗作用较小，但不影响CCR1、CCR3或CCR4。因此，TAK-779对R5 HIV-1复制表现出高效且选择性的抑制，而对宿主细胞未显示任何细胞毒性。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临床分离株以及一株实验室毒株的复制，尽管它对T细胞系嗜性（利用CXCR4或X4）HIV-1完全无活性。
