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首页> 外文期刊>Biochemical Pharmacology >Molecular cloning and radioligand binding characterization of the chemokine receptor CCR5 from rhesus macaque and human.
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Molecular cloning and radioligand binding characterization of the chemokine receptor CCR5 from rhesus macaque and human.

机译：恒河猴和人趋化因子受体CCR5的分子克隆和放射性配体结合特征。

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The aim of this study was to determine if macaque represents a suitable species for the pre-clinical evaluation of novel CCR5 antagonists, such as maraviroc (UK-427,857). To do this we cloned and expressed CCR5 from rhesus macaque and compared the binding properties of [125I]-MIP-1beta and [3H]-maraviroc with human recombinant CCR5. [125I]-MIP-1beta bound with similar high affinity to CCR5 from macaque (K(d) = 0.24 +/- 0.05 nM) and human (K(d) = 0.23 +/- 0.05 nM) and with similar kinetic properties. In competition binding studies the affinity of a range of human chemokines for macaque CCR5 was also similar to human CCR5. Maraviroc inhibited binding of [125I]-MIP-1beta to CCR5 from macaque and human with similar potency (IC50 = 17.50 +/- 1.24 nM and 7.18 +/- 0.93 nM, respectively) and antagonised MIP-1beta induced intracellular calcium release mediated through CCR5 from macaque and human with similar potency (IC50 = 17.50 +/- 3.30 nM and 12.07 +/- 1.89, respectively). [3H]-maraviroc bound with high affinity to CCR5 from macaque (K(d) = 1.36+/-0.07 nM) and human (K(d) = 0.86 +/- 0.08 nM), but was found to dissociate approximately 10-fold more quickly from macaque CCR5. However, as with the human receptor, maraviroc was shown to be a high affinity, potent functional antagonist of macaque CCR5 thereby indicating that the macaque should be a suitable species in which to evaluate the pharmacology, safety and potential mechanism-related toxicology of novel CCR5 antagonists.
机译：这项研究的目的是确定猕猴是否代表合适的物种用于新型CCR5拮抗剂（如maraviroc（UK-427,857））的临床前评估。为此，我们从猕猴克隆并表达了CCR5，并比较了[125I] -MIP-1beta和[3H] -maraviroc与人重组CCR5的结合特性。 [125I] -MIP-1beta与猕猴（K（d）= 0.24 +/- 0.05 nM）和人（K（d）= 0.23 +/- 0.05 nM）的CCR5具有相似的高亲和力，并且具有相似的动力学特性。在竞争结合研究中，一系列人类趋化因子对猕猴CCR5的亲和力也与人类CCR5相似。 Maraviroc抑制了猕猴和人的[125I] -MIP-1beta与CCR5的结合，效力相似（IC50分别为17.50 +/- 1.24 nM和7.18 +/- 0.93 nM），并且拮抗了MIP-1beta诱导的细胞内钙释放通过来自猕猴和人的CCR5，效价相似（IC50分别为17.50 +/- 3.30 nM和12.07 +/- 1.89）。 [3H] -maraviroc与猕猴（K（d）= 1.36 +/- 0.07 nM）和人（K（d）= 0.86 +/- 0.08 nM）的CCR5具有高亲和力结合，但发现其解离约10-从猕猴CCR5折叠起来更快。但是，与人类受体一样，maraviroc被证明是猕猴CCR5的一种高亲和力，功能强大的拮抗剂，从而表明猕猴应该是一种合适的物种，可在其中评估新型CCR5的药理学，安全性和潜在的机制相关毒理学拮抗剂。

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