Highly potent inhibition of human immunodeficiency virus type 1 replication by TAK-220, an orally bioavailable small-molecule CCR5 antagonist
Highly potent inhibition of human immunodeficiency virus type 1 replication by TAK-220, an orally bioavailable small-molecule CCR5 antagonist
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DOI：
10.1128/aac.49.8.3474-3482.2005
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发表时间：
2005-08-01
影响因子：
4.9
通讯作者：
Baba, M
中科院分区：
文献类型：
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作者：
Takashima, K;Miyake, H;Baba, M
TAK-220是一类新型趋化因子受体拮抗剂的成员，通过受体结合和钙动员试验测定，对CCR 5具有高度特异性。该化合物选择性抑制辅助受体介导的人类免疫缺陷病毒1型（HIV-1）进入宿主细胞和CCR 5介导的HIV-1感染。TAK-220可抑制6种使用CCR 5的（115）HIV-1临床分离株在外周血单核细胞（PBMC）中的复制，平均90%有效浓度为13 nM。TAK-220的抗HIV-1活性不受加入高浓度人血清的影响。它同样抑制R5 HIV-1在从8个不同供体获得的PBMC中的复制，而与病毒产生水平无关。此外，发现TAK-220的抗HIV-1活性不依赖于亚型。TAK-220未诱导CCR 5内化，但阻断了两种单克隆抗体的结合，这两种单克隆抗体可识别CCR 5表达细胞中CCR 5的第二个细胞外环。这些结果表明，TAK-220通过干扰辅助受体介导的病毒进入宿主细胞，选择性抑制R5 HIV-1复制。在5 mg/kg体重剂量下，TAK-220在大鼠和猴中的经口生物利用度分别为9.5%和28.9%。因此，TAK-220是治疗HIV-1感染的有前景的候选药物。
TAK-220 is a member of a novel class of chemokine receptor antagonists and is highly specific to CCR5, as determined by receptor binding and calcium mobilization assays. The compound selectively inhibited coreceptor-mediated entry of human immunodeficiency virus type 1 (HIV-1) into host cells and HIV-1 infection mediated by CCR5. TAK-220 inhibited the replication of six CCR5-using (115) HIV-1 clinical isolates in peripheral blood mononuclear cells (PBMCs) with a mean 90% effective concentration of 13 nM. The anti-HIV-1 activity of TAK-220 was not affected by addition of high concentrations of human serum. It equally inhibited R5 HIV-1 replication in PBMCs obtained from eight different donors, irrespective of the levels of viral production. Furthermore, the anti-HIV-1 activity of TAK-220 was found to be subtype independent. TAK-220 did not induce CCR5 internalization but blocked the binding of two monoclonal antibodies that recognize the second extracellular loop of CCR5 in CCR5-expressing cells. These results suggest that TAK-220 selectively inhibits R5 HIV-1 replication by interfering with coreceptor-mediated entry of the virus into host cells. At a dose of 5 mg/kg of body weight, TAK-220 showed oral bioavailabilities of 9.5 and 28.9% in rats and monkeys, respectively. Thus, TAK-220 is a promising candidate for the treatment of HIV-1 infection.