Cyclosporin A is an immunosuppressive agent which has three major cellular targets including cyclophilins, calcineurin and transporters[1] while it can inhibit the activity of cyclophilin A and calcineurin with an IC50 of 360nM[1] and 5nM[2]. Cyclosporin A-mediated immunosuppression is achieved by forming a ternary complex with cyclophilins and calcineurin to block the phosphatase activity of calcineurin and thus dephosphorylation and nuclear shuttling of the nuclear factor of activated T-cells (NFAT) is inhibited [1, 3]. Cyclosporine A is mainly used in clinical practice to inhibit immune failure in xenograft tissues [1].
Cyclosporin A (0.001nM~1mM; 24h) inhibited production of IL-2 in Jurkat cells stimulated with OKT3 monoclonal antibody and PMA (phorbol 12-myristate 13-acetate) with an IC50 of 10nM [2]; Cyclosporin A (4μM; 18h) reduced viral envelope protein secretion from hepatitis B virus-infected HepaRG cells [1]; Cyclosporin A (10μM; 24h) reduced viral gene expression and viral titers significantly in human bronchial epithelial cells (HBEpCs) infected with SARS-CoV-2 [4].
Cyclosporin A (50mg/kg; 6d; p.o.) reduced viral RNA in Balb/c mice infected with SARS-CoV-2 [4]; Cyclosporin A (10mg/kg; 2d/tid.; p.o.) significantly reduced the accumulation of eosinophils in the lung of male Hartley guinea-pig which were sensitized by ovalbumin [5]; Cyclosporin A (5mg/kg; 3weeks; p.o.) increased the serum creatinine and blood urea nitrogen (BUN) levels in male Wistar rats [6].
References:
[1] Watashi K, Sluder A, Daito T, et al. Cyclosporin A and its analogs inhibit hepatitis B virus entry into cultured hepatocytes through targeting a membrane transporter, sodium taurocholate cotransporting polypeptide (NTCP) [J]. Hepatology, 2014, 59(5): 1726-1737.
[2] Fruman D A, Klee Cb F-Bierer B E, Bierer Be F-Burakoff S J, et al. Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A [J]. Proceedings of the National Academy of Sciences of the United States of America, 1992, 89(9): 3686-3690.
[3] Schiene-Fischer C, Fischer G, Braun M, et al. Non-immunosuppressive cyclophilin inhibitors [J]. Angewandte Chemie, 2022, 61(39): e202201597.
[4] Sauerhering L, Kuznetsova I, Kupke A, et al. Cyclosporin A reveals potent antiviral effects in preclinical models of SARS-CoV-2 Infection [J]. American Journal of Respiratory and Critical Care Medicine, 2022, 205(8): 964-968.
[5] Lagente V, Carré C, Kyriacopoulos F, et al. Inhibitory effect of cyclosporin A on eosinophil infiltration in the guinea-pig lung induced by antigen, platelet-activating factor and leukotriene B4 [J]. The European Respiratory Journal, 1994, 7(5): 921-926.
[6] Sereno J, Rodrigues-Santos P, Vala H, et al. Transition from cyclosporine-induced renal dysfunction to nephrotoxicity in an in vivo rat model [J]. International journal of molecular sciences, 2014, 15(5): 8979-8997.
Cyclosporin A是一种免疫抑制剂，其主要的三个靶点是亲环蛋白、钙调神经磷酸酶和转运蛋白[1]，其抑制亲环蛋白A和钙调神经磷酸酶活性的IC50分别为360nM[1]和5nM[2]。Cyclosporin A介导的免疫抑制是通过与亲环蛋白和钙调磷酸酶形成三元复合物来阻断钙调磷酸酶的活性，从而抑制NFAT（nuclear factor of activated T-cells）的去磷酸化和阻止其转位至细胞核[1, 3]。Cyclosporin A在临床上主要用于抑制异种移植组织的免疫衰竭[1]。
Cyclosporin A（0.001nM~1mM；24h）抑制OKT3单克隆抗体和PMA（phorbol 12-myristate 13-acetate）刺激的Jurkat cells产生IL-2的IC50为10nM[2]；Cyclosporin A（4μM；18h）减少乙型肝炎病毒感染的HepaRG细胞分泌病毒包膜蛋白[1]；Cyclosporin A（10μM；24h）显著降低了SARS-CoV-2感染的HBEpCs（human bronchial epithelial cells）中的病毒基因表达和病毒滴度[4]。
Cyclosporin A（50mg/kg；6d；p.o.）降低了SARS-CoV-2感染的Balb/c小鼠体内的病毒RNA[4]；Cyclosporin A（10mg/kg；2d/tid.；p.o.）显著减少了卵清蛋白致敏的雄性Hartley豚鼠肺内的嗜酸性粒细胞聚集[5]；Cyclosporin A（5mg/kg；3weeks；p.o.）增加了雄性Wistar大鼠的血清肌酐和尿素氮水平[6]。