PMX 53 is a potent, cell-permeable, and orally active C5a receptor (CD88) antagonist with an IC50 value of 20nM[1]. PMX 53 specifically binds to C5aR1, blocking the interaction between complement C5a and its receptor, thereby inhibiting C5a-induced inflammatory responses such as myeloperoxidase (MPO) release and neutrophil chemotaxis. PMX 53 also acts as a low-affinity agonist for MrgX2 and can stimulate MrgX2-mediated mast cell degranulation at higher concentrations[1, 2]. PMX 53 is commonly used in research on inflammatory mechanisms in autoimmune diseases, sepsis, neurodegenerative diseases, and psoriasis[3].
In vitro, pre-incubation of C57BL/6J mouse neutrophils with PMX 53 (10μM) for 1h, followed by stimulation with recombinant murine C5a (0.1μM) for 3h, inhibited C5a-induced NETosis[4]. The addition of PMX 53 (50, 100, 150nM) to the culture medium of THP-1 and HL-60 cells prior to treatment with LukS-PV (1μM) for 24h led to a concentration-dependent suppression of LukS-PV-induced apoptosis[5].
In vivo, intravenous administration of PMX 53 (1mg/kg) via the femoral vein 30min before ischemia in Sprague-Dawley rats significantly reduced MPO activity in spinal cord tissue 48h after reperfusion[6]. Oral administration of PMX 53 (10mg/kg/day) to C57BL/6 mice, starting 2 days before intracerebral hemorrhage and continuing for 5 days, significantly decreased mRNA levels of TNF-α, IL-6, and iNOS in perihematomal tissues[7]. Subcutaneous injection of PMX 53 (3mg/kg) 30min before seizure stimulation in fully kindled CD1 mice reduced the proportion of mice experiencing stage 5 seizures by 50%[8].
References:
[1] SUBRAMANIAN H, KASHEM S W, COLLINGTON S J, et al. PMX-53 as a dual CD88 antagonist and an agonist for Mas-related gene 2 (MrgX2) in human mast cells[J]. Molecular pharmacology, 2011, 79(6): 1005-1013.
[2] DICK J, GAN P Y, FORD S L, et al. C5a receptor 1 promotes autoimmunity, neutrophil dysfunction and injury in experimental anti-myeloperoxidase glomerulonephritis[J]. Kidney international, 2018, 93(3): 615-625.
[3] KÖHL J. Drug evaluation: the C5a receptor antagonist PMX-53[J]. Current opinion in molecular therapeutics, 2006, 8(6): 529-538.
[4] CHEN Y, LI X, LIN X, et al. Complement C5a induces the generation of neutrophil extracellular traps by inhibiting mitochondrial STAT3 to promote the development of arterial thrombosis[J]. Thrombosis journal, 2022, 20(1): 24.
[5] ZHANG P, YU W W, PENG J, et al. LukS-PV induces apoptosis in acute myeloid leukemia cells mediated by C5a receptor[J]. Cancer medicine, 2019, 8(5): 2474-2483.
[6] DONG Q, SUN L, PEN L, et al. PMX53 protects spinal cord from ischemia-reperfusion injury in rats in the short term[J]. Spinal Cord, 2016, 54(4): 254-258.
[7] LI G, FAN R M, CHEN J L, et al. Neuroprotective effects of argatroban and C5a receptor antagonist (PMX53) following intracerebral haemorrhage[J]. Clinical & Experimental Immunology, 2014, 175(2): 285-295.
[8] BENSON M J, THOMAS N K, TALWAR S, et al. A novel anticonvulsant mechanism via inhibition of complement receptor C5ar1 in murine epilepsy models[J]. Neurobiology of disease, 2015, 76: 87-97.
PMX 53是一种高效且具有细胞渗透性和口服活性的C5a受体（CD88）拮抗剂，IC50值为20nM[1]。PMX 53能特异性结合C5aR1，阻断补体C5a与受体的结合，从而抑制C5a诱导的髓过氧化物酶（MPO）释放和中性粒细胞趋化作用等炎症反应。PMX 53也是一种低亲和力的MrgX2激动剂，在较高浓度时可刺激MrgX2介导的肥大细胞脱颗粒[1,2]。PMX 53通常用于自身免疫性疾病、败血症、神经退行性疾病和牛皮藓等疾病的炎症机制研究[3]。
在体外，PMX 53（10μM）与C57BL/6J小鼠中性粒细胞孵育1h，随后加入重组小鼠C5a（0.1μM）刺激3h，能抑制C5a诱导的NETosis[4]。PMX 53（50, 100, 150nM）在LukS-PV处理前加入到THP-1和HL-60细胞的培养基中，后加入LukS-PV（1μM）共同培养24h，PMX 53以浓度依赖的方式显著抑制了LukS-PV诱导的细胞凋亡[5]。
在体内，PMX 53（1mg/kg）于Sprague-Dawley大鼠缺血前30min经股静脉注射给药，显著降低了大鼠再灌注后48h脊髓组织中MPO的活性[6]。PMX 53（10mg/kg/day）于脑出血前2天开始通过口服给药C57BL/6小鼠，并持续治疗5天，显著降低了血肿周围组织中TNF-α、IL-6和iNOS的mRNA水平[7]。PMX 53（3mg/kg）在癫痫刺激前30min皮下注射给药已完全角膜点燃的CD1小鼠，使经历第5级癫痫发作的小鼠比例降低了50%[8]。