2-芳基丙酸类CXC趋化因子受体1（CXCR1）配体作为新型非竞争性CXCL8抑制剂
2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors.
作者信息
Allegretti Marcello, Bertini Riccardo, Cesta Maria Candida, Bizzarri Cinzia, Di Bitondo Rosa, Di Cioccio Vito, Galliera Emanuela, Berdini Valerio, Topai Alessandra, Zampella Giuseppe, Russo Vincenzo, Di Bello Nicoletta, Nano Giuseppe, Nicolini Luca, Locati Massimo, Fantucci Piercarlo, Florio Saverio, Colotta Francesco
机构信息
Dompé Research and Development, Dompé S.p.A., via Campo di Pile, 67100, L'Aquila, Italy.
出版信息
J Med Chem. 2005 Jun 30;48(13):4312-31. doi: 10.1021/jm049082i.
The CXC chemokine CXCL8/IL-8 plays a major role in the activation and recruitment of polymorphonuclear (PMN) cells at inflammatory sites. CXCL8 activates PMNs by binding the seven-transmembrane (7-TM) G-protein-coupled receptors CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2). (R)-Ketoprofen (1) was previously reported to be a potent and specific noncompetitive inhibitor of CXCL8-induced human PMNs chemotaxis. We report here molecular modeling studies showing a putative interaction site of 1 in the TM region of CXCR1. The binding model was confirmed by alanine scanning mutagenesis and photoaffinity labeling experiments. The molecular model driven medicinal chemistry optimization of 1 led to a new class of potent and specific inhibitors of CXCL8 biological activity. Among these, repertaxin (13) was selected as a clinical candidate drug for prevention of post-ischemia reperfusion injury.
CXC趋化因子CXCL8/IL-8在炎症部位多形核（PMN）细胞的激活和募集中起主要作用。CXCL8通过结合七跨膜（7-TM）G蛋白偶联受体CXC趋化因子受体1（CXCR1）和CXC趋化因子受体2（CXCR2）来激活PMN。据先前报道，（R）-酮洛芬（1）是CXCL8诱导的人PMN趋化性的一种强效且特异性的非竞争性抑制剂。我们在此报告分子建模研究，该研究显示了1在CXCR1跨膜区域的一个假定相互作用位点。通过丙氨酸扫描诱变和光亲和标记实验证实了该结合模型。基于分子模型驱动的1的药物化学优化产生了一类新的CXCL8生物活性的强效且特异性抑制剂。其中，瑞帕昔明（13）被选为预防缺血后再灌注损伤的候选药物。
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