Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-Chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro
Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-Chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro
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DOI：
10.1128/jvi.78.16.8654-8662.2004
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发表时间：
2004-08-01
影响因子：
5.4
通讯作者：
Mitsuya, H
中科院分区：
文献类型：
--
作者：
Maeda, K;Nakata, H;Mitsuya, H
我们鉴定出一种新的spirodiketopiperazine （SDP）衍生物AK602/ON04128/GW873140，它特异性地以高亲和力（K-d约为3 nM）阻断巨噬细胞炎症蛋白1alpha （MIP-1alpha）与CCR5的结合，有效地阻断人类免疫缺陷病毒1型（HIV-1） gp120/CCR5的结合，并对广泛的实验室和原代R5 HIV-1分离株发挥有效活性。包括耐多药HIV-1(HIV-1(MDR))（50%的体外抑制浓度为0.1 ~ 0.6 nM）。AK602竞争性地阻断了中国仓鼠卵巢细胞上表达的两种单克隆抗体与CCR5的结合，分别是针对CCR5多结构域表位的45523和针对CCR5第二细胞外环（ECL2B） c端一半的45531。尽管AK602的抗hiv -1活性远高于其他先前发表的CCR5抑制剂，包括TAK-779和SCH-C，但AK602保留了RANTES（激活正常t细胞表达和分泌）和mip -1 β与CCR5（+）细胞的结合及其功能，包括cc趋化因子诱导的趋化和CCR5内化，而TAK-779和SCH-C完全阻断了cc趋化因子/CCR5的相互作用。药代动力学研究显示在啮齿类动物中具有良好的口服生物利用度。这些数据为进一步开发AK602作为HIV-1感染的潜在治疗药物提供了依据。
We identified a novel spirodiketopiperazine (SDP) derivative, AK602/ON04128/GW873140, which specifically blocked the binding of macrophage inflammatory protein 1alpha (MIP-1alpha) to CCR5 with a high affinity (K-d of approximate to3 nM), potently blocked human immunodeficiency virus type 1 (HIV-1) gp120/CCR5 binding and exerted potent activity against a wide spectrum of laboratory and primary R5 HIV-1 isolates, including multidrug-resistant HIV-1 (HIV-1(MDR)) (50% inhibitory concentration values of 0.1 to 0.6 nM) in vitro. AK602 competitively blocked the binding to CCR5 expressed on Chinese hamster ovary cells of two monoclonal antibodies, 45523, directed against multidomain epitopes of CCR5, and 45531, specific against the C-terminal half of the second extracellular loop (ECL2B) of CCR5. AK602, despite its much greater anti-HIV-1 activity than other previously published CCR5 inhibitors, including TAK-779 and SCH-C, preserved RANTES (regulated on activation normal T-cell expressed and secreted) and MIP-1beta binding to CCR5(+) cells and their functions, including CC-chemokine-induced chemotaxis and CCR5 internalization, while TAK-779 and SCH-C fully blocked the CC-chemokine/CCR5 interactions. Pharmacokinetic studies revealed favorable oral bioavailability in rodents. These data warrant further development of AK602 as a potential therapeutic for HIV-1 infection.