Pharmacological evidence for complex and multiple site interaction of CXCR4 with SDF-1α:: implications for development of selective CXCR4 antagonists
Pharmacological evidence for complex and multiple site interaction of CXCR4 with SDF-1α:: implications for development of selective CXCR4 antagonists
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DOI：
10.1016/s0165-2478(01)00228-0
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发表时间：
2001-08-01
影响因子：
4.4
通讯作者：
Aiyar, N
中科院分区：
文献类型：
--
作者：
Gupta, SK;Pillarisetti, K;Aiyar, N
C-X-C趋化因子SDF-1及其受体CXCR4在HIV-1感染和血管炎性疾病的病理生理中起关键作用。在本研究中，我们研究了人白血病细胞系中SDF-1 α与CXCR4相互作用的药理学特性。我们的数据，基于[I-125]-SDF-1 α放射配体结合，SDF-1 α诱导的[S-35]-GTP γ - ma结合和特异性CXCR4拮抗剂AMD3100的使用，揭示了SDF-1 α -CXCR4相互作用的复杂性。首先，与冷SDF-1 α的同源竞争显示出双峰配体位移曲线；其次，尽管AMD3100以高亲和力抑制SDF-1 α介导的趋化性（IC50=4.7 nM）和[S-35]-GTP γ - ma结合（IC50=7.4 nM），但在放射性配体结合试验中，其效价高达3000倍（IC50= 15.2 nM）。这些结果为最近描述的SDF-1 α -CXCR4相互作用的两个位点模型提供了药理学证据。因此，抑制sdf - 1 α与一个受体位点的结合足以拮抗功能，而不会导致其完全脱离受体。此外，这些发现对开发和评估用于治疗用途的cxcr4选择性小分子拮抗剂具有重要意义。(C) 2001 Elsevier Science B.V.版权所有
The C-X-C chemokine SDF-1 and its receptor CXCR4, mediate a pivotal role in the pathophysiology of HIV-1 infection and vascular inflammatory diseases. in this study, we investigated the pharmacological properties of SDF-1 alpha interaction with CXCR4 in human leukemia cell lines. Our data, based on [I-125]-SDF-1 alpha radioligand binding, SDF-1 alpha -induced [S-35]-GTP gammaS binding and use of specific CXCR4 antagonist AMD3100 reveals the complex nature of SDF-1 alpha -CXCR4 interaction. Firstly, homologous competition with cold SDF-1 alpha revealed a bimodal ligand displacement curve and secondly, although AMD3100 inhibited both SDF-1 alpha -mediated chemotaxis (IC50=4.7 nM) and [S-35]-GTP gammaS binding (IC50=7.4 nM) with high affinity, it was intriguingly upto 3000-fold less potent (IC50 = 15.2 muM) in the radioligand binding assay. These results provide pharmacological evidence for the recently described two-site model for SDF-1 alpha -CXCR4 interaction. Accordingly, inhibition of SDF-l alpha binding to one of the receptor sites is sufficient to antagonize function, without causing its complete displacement from the receptor. Furthermore, these findings have important implications in the development and evaluation or CXCR4-selective small molecule antagonists for therapeutic use. (C) 2001 Elsevier Science B.V. All rights reserved.