Small neutralizing molecules to inhibit actions of the chemokine CXCL12
Small neutralizing molecules to inhibit actions of the chemokine CXCL12
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DOI：
10.1074/jbc.m803947200
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发表时间：
2008-08-22
影响因子：
4.8
通讯作者：
Galzi, Jean-luc
中科院分区：
文献类型：
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作者：
Hachet-Haas, Muriel;Balabanian, Karl;Galzi, Jean-luc
趋化因子CXCL12和受体CXCR4在正常血管和神经元发育、炎症反应以及感染性疾病和癌症中起关键作用。例如，CXCL12已被证明介导人类免疫缺陷病毒诱导的神经毒性、增殖性视网膜病和慢性炎症，而其受体CXCR4参与人类免疫缺陷病毒感染、癌症转移和称为疣、低丙种球蛋白血症、免疫缺陷和骨髓增生异常（WHIM）综合征的罕见疾病。当我们筛选化学库以寻找CXCL 12与受体CXCR 4之间相互作用的抑制剂时，我们鉴定了来自查尔酮家族的合成化合物，这些化合物可以减少CXCL 12与CXCR 4的结合，抑制受体介导的钙反应，并阻止CXCR 4响应CXCL 12的内化。我们发现，这些化合物显示出一种原始的作用机制，因为它们与趋化因子结合，但不与CXCR4结合。最高亲和力的分子阻断人外周血淋巴细胞的体外趋化性。它在过敏性嗜酸性气道炎症小鼠模型中也具有体内活性，我们在该模型中检测到炎症浸润的抑制作用。该化合物显示出对CXCL12的选择性，而不是对CCL5和CXCL8趋化因子的选择性，并阻断了CXCL12与其第二受体CXCR7的结合。与中和抗体的作用类似，这种分子表现为一种小的有机中和化合物，可能证明具有宝贵的药理学和治疗潜力。
The chemokine CXCL12 and the receptor CXCR4 play pivotal roles in normal vascular and neuronal development, in inflammatory responses, and in infectious diseases and cancer. For instance, CXCL12 has been shown to mediate human immunodeficiency virus-induced neurotoxicity, proliferative retinopathy and chronic inflammation, whereas its receptor CXCR4 is involved in human immunodeficiency virus infection, cancer metastasis and in the rare disease known as the warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis (WHIM) syndrome. As we screened chemical libraries to find inhibitors of the interaction between CXCL12 and the receptor CXCR4, we identified synthetic compounds from the family of chalcones that reduce binding of CXCL12 to CXCR4, inhibit calcium responses mediated by the receptor, and prevent CXCR4 internalization in response to CXCL12. We found that the chemical compounds display an original mechanism of action as they bind to the chemokine but not to CXCR4. The highest affinity molecule blocked chemotaxis of human peripheral blood lymphocytes ex vivo. It was also active in vivo in a mouse model of allergic eosinophilic airway inflammation in which we detected inhibition of the inflammatory infiltrate. The compound showed selectivity for CXCL12 and not for CCL5 and CXCL8 chemokines and blocked CXCL12 binding to its second receptor, CXCR7. By analogy to the effect of neutralizing antibodies, this molecule behaves as a small organic neutralizing compound that may prove to have valuable pharmacological and therapeutic potential.