Laboratoire d'Innovation Thérapeutique, UMR 7200 CNRS/Université de Strasbourg, Faculté de Pharmacie, 74 Route du Rhin, 67401 Illkirch, France.
J Biol Chem. 2013 Apr 26;288(17):11865-76. doi: 10.1074/jbc.M112.449348. Epub 2013 Feb 28.
The chemokine receptor CXCR4 and its chemokine CXCL12 are involved in normal tissue patterning but also in tumor cell growth and survival as well as in the recruitment of immune and inflammatory cells, as successfully demonstrated using agents that block either CXCL12 or CXCR4. In order to achieve selectivity in drug action on the CXCR4/CXCL12 pair, in particular in the airways, drugs should be delivered as selectively as possible in the treated tissue and should not diffuse in the systemic circulation, where it may reach undesired organs. To this end, we used a previously unexploited Knoevenagel reaction to create a short lived drug, or soft drug, based on the CXCL12-neutralizing small molecule, chalcone 4, which blocks binding of CXCL12 to CXCR4. We show that the compound, carbonitrile-chalcone 4, blocks the recruitment of eosinophils to the airways in ovalbumin-sensitized and challenged mice in vivo when administered directly to the airways by the intranasal route, but not when administered systemically by the intraperitoneal route. We show that the lack of effect at a distant site is due to the rapid degradation of the molecule to inactive fragments. This approach allows selective action of the CXCL12 neutraligands although the target protein is widely distributed in the organism.
趋化因子受体 CXCR4 及其趋化因子 CXCL12 参与正常组织形态发生，但也参与肿瘤细胞的生长和存活以及免疫和炎症细胞的募集，这已成功地使用阻断 CXCL12 或 CXCR4 的试剂证明。为了在 CXCR4/CXCL12 对药物作用中实现选择性，特别是在气道中，药物应该尽可能选择性地递送到治疗组织中，并且不应在全身循环中扩散，因为它可能到达不需要的器官。为此，我们使用了以前未被利用的 Knoevenagel 反应，基于趋化因子 CXCL12 中和小分子查尔酮 4 ，创建了一种短寿命药物，或软药物，该药物可阻断 CXCL12 与 CXCR4 的结合。我们表明，当通过鼻内途径直接施用于气道时，化合物腈基-查尔酮 4 可阻断卵清蛋白致敏和挑战小鼠气道中嗜酸性粒细胞的募集，但当通过腹膜内途径系统给药时则不会。我们表明，在远处部位缺乏作用是由于该分子迅速降解为无活性片段。尽管靶蛋白在体内广泛分布，但这种方法允许 CXCL12 中和配体的选择性作用。
