Studies on the interactions between lactam analogs and the N‐terminal extracellular tail of CC chemokine receptor 4 by CZE
Studies on the interactions between lactam analogs and the N‐terminal extracellular tail of CC chemokine receptor 4 by CZE
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DOI：
10.1002/elps.200700258
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发表时间：
2007-07
期刊：
影响因子：
2.9
通讯作者：
Zhe Sun;Xiaomei Ling;Wei Sun;Jun-hai Xiao;Caihua Yin;Ying Wang
中科院分区：
文献类型：
--
作者：
Zhe Sun;Xiaomei Ling;Wei Sun;Jun-hai Xiao;Caihua Yin;Ying Wang
CC趋化因子受体4（CCR4）是一种具有特征性七跨膜结构的G蛋白偶联受体，选择性表达在Th2型CD4+ T细胞上，在过敏性炎症中发挥着关键作用。在这项研究中，CZE 首次研究了已知的 CCR4 拮抗剂 2-(2-(2,4-二氯-苯基)-4-{[(2-甲基-3-氯-苯基)-1-基甲基]-氨基甲酰基}-甲基)-5-氧代-吡咯-1-基)-N-(3-哌啶基-丙基)-乙酰胺（化合物 A）与 ML40 之间的相互作用。确定了药物-肽结合的定性和定量特征。通过斯卡查德图回归计算，化合物A的反式非对映异构体与ML40之间相互作用的结合常数为(1.06±0.11)×105/M。此外，还证实反式非对映异构体与 CCR4 的亲和力比顺式非对映异构体更强。实验结果表明，CZE报道的测定化合物A与ML40相互作用的方法强大、灵敏、快速，所需试剂用量较少，可作为过敏性炎症疾病药物研发中一系列内酰胺类似物的可靠筛选方法之一。
CC chemokine receptor 4 (CCR4) is a kind of G‐protein‐coupled receptors with a characteristic seven‐transmembrane structure and selectively expressed on Th2‐type CD4+ T‐cells, which play a pivotal role in allergic inflammation. In this study, the interactions between 2‐(2‐(2,4‐dichloro‐phenyl)‐4‐{[(2‐methyl‐3‐chloro‐phenyl)‐1‐ylmethyl]‐carbamoyl}‐methyl)‐5‐oxo‐pyrrole‐1‐yl)‐N‐(3‐piperidinyl‐propyl)‐acetamide (compound A), a known CCR4 antagonist, and ML40 were studied by CZE for the first time. Both qualitative and quantitative characterizations of the drug–peptide binding were determined. The binding constant of the interaction between the trans‐diastereomer of compound A and ML40, calculated from the Scatchard plot by regression, was (1.06 ± 0.11)×105/M. Also, it was confirmed that the trans‐diastereomer was more potent affinity with CCR4 than its cis‐counterpart. The experimental results show that this reported method by CZE for the determination of the compound A and ML40 interactions is powerful, sensitive, and fast, requires less amounts of reagents, and further, it can be employed as one of the reliable screening methods to a series of lactam analogs in the drug discovery for allergic inflammation diseases.