Reparixin L-lysine salt is a small molecule, allosteric noncompetitive inhibitor of CXCR1 and CXCR2 chemokine receptors involved in inflammation[1]. Reparixin is 400 folds more effective than CXCR2 in inhibiting CXCR1 activity[2]. Reparixin efficiently inhibits the biological events triggered by CXCL8 by binding to the transmembrane (TM) region of CXCR1 in an allosteric cavity within the helixes TM1, 2, 3, 6 and 7[2].
In vitro, the sensitivity to Reparixin-mediated inhibition of CXCL8-induced chemotaxis was reduced in L1.2 cells transfected with the mutant CXCR1 (Ile43Val) (IC50 values of 5.6×10-9M and 8.0×10-8M for CXCR1 WT and CXCR1 Ile43Val, respectively)[3]. The IC50 values of Reparixin for inhibiting CINC-1 and CXCL8-induced rat neutrophil migration were 6 and 30nM, respectively[4].
In vivo, Reparixin (3-30mg/kg; i.v.) inhibited, in a dose-dependent manner, the increase in vascular permeability in the intestine and lungs and the recruitment of neutrophils after ischemic SMA reperfusion in mice[4]. Reparixin treatment at 30mg/kg subcutaneously alleviated PM and bleomycin-induced pulmonary fibrosis phenotypes in mice[5].
References:
[1] Marsh DR, Flemming JM. Inhibition of CXCR1 and CXCR2 chemokine receptors attenuates acute inflammation, preserves gray matter and diminishes autonomic dysreflexia after spinal cord injury. Spinal Cord. 2011;49(3):337-344.
[2] Bertini R, Barcelos LS, Beccari AR, et al. Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor. Br J Pharmacol. 2012;165(2):436-454.
[3] Moriconi A, Cesta MC, Cervellera MN, et al. Design of noncompetitive interleukin-8 inhibitors acting on CXCR1 and CXCR2. J Med Chem. 2007;50(17):3984-4002.
[4] Souza DG, Bertini R, Vieira AT, et al. Repertaxin, a novel inhibitor of rat CXCR2 function, inhibits inflammatory responses that follow intestinal ischaemia and reperfusion injury. Br J Pharmacol. 2004;143(1):132-142.
[5] Cheng IY, Liu CC, Lin JH, et al. Particulate Matter Increases the Severity of Bleomycin-Induced Pulmonary Fibrosis through KC-Mediated Neutrophil Chemotaxis. Int J Mol Sci. 2019;21(1):227.
Reparixin L-lysine salt是一种参与炎症反应的CXCR1和CXCR2趋化因子受体的小分子变构非竞争性抑制剂[1]。Reparixin抑制CXCR1活性的效率是CXCR2的400倍[2]。Reparixin能够通过与CXCR1蛋白的跨膜区域（位于TM1、2、3、6和7螺旋结构内的别构腔）结合的方式，有效地抑制由CXCL8引发的生物过程[2]。
体外实验中，在转染了突变型 CXCR1（Ile43Val）的L1.2细胞中，Reparixin对CXCL8诱导的细胞趋化作用的抑制敏感性降低（CXCR1 WT和CXCR1 Ile43Val的IC50值分别为5.6×10-9M和8.0×10-8M）[3]。Reparixin抑制CINC-1和CXCL8诱导的大鼠嗜中性粒细胞迁移的IC50值分别为6和30nM[4]。
体内实验中，Reparixin（3-30mg/kg；静脉注射）以剂量依赖的方式抑制小鼠SMA缺血再灌注后肠和肺血管通透性的增加和中性粒细胞的募集[4]。Reparixin以30mg/kg皮下注射给药，可减轻小鼠中由颗粒物（PM）和博来霉素（bleomycin） 诱导的肺纤维化表型。