CU CPT 4a is a potent inhibitor of toll-like receptor 3 (TLR3), with an IC50 value of 3.44μM [1]. CU CPT 4a suppresses the downstream signaling pathways mediated by TLR3/dsRNA complex, resulting in inhibition of interferons and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) production[2]. CU CPT 4a has been widely used to regulate TLR3-mediated inflammation in animal models[3].
In vitro, CU CPT 4a pretreatment at 40μM for 1 hour significantly inhibited invasion of KKU213 cells induced by 2.5μg/ml Poly(I:C) (12h)[4]. CU CPT 4a treatment at 20µM for 1h significantly inhibited Tributyltin (TBT) (25nM)-induced IL-1β and IL-6 production in human peripheral blood mononuclear cells (PBMCs) [5]. CU CPT 4a treatment (10µM) for 24h abolished the stimulatory effect of histamine on TBK1/IRF3 signaling in SARS-CoV-2-infected Caco2 cells[6]. Treatment with 40μM CU CPT 4a for 24 hours reduced Caspase-3/7 activation without attenuating LPS-stimulated apoptosis in mouse cardiomyocytes[7].
In vivo, CU CPT 4a treatment via intraperitoneally injection (30μg/10μl; three times within 5 days) significantly caused delayed development and decreased intensity of clinical signs and pathological lesions, low viral load, significantly reduced Negri bodies (NBs) formation, and increased survival time in SRABV-infected mice[8].
References:
[1] Wang Y, Zhang S, Li H, et al. Small-molecule modulators of toll-like receptors[J]. Accounts of chemical research, 2020, 53(5): 1046-1055.
[2] Cheng K, Wang X, Yin H. Small-molecule inhibitors of the TLR3/dsRNA complex[J]. Journal of the American Chemical Society, 2011, 133(11): 3764-3767.
[3] Takemura N, Kawasaki T, Kunisawa J, et al. Blockade of TLR3 protects mice from lethal radiation-induced gastrointestinal syndrome[J]. Nature communications, 2014, 5(1): 3492.
[4] Lomphithak T, Choksi S, Mutirangura A, et al. Receptor-interacting protein kinase 1 is a key mediator in TLR3 ligand and Smac mimetic-induced cell death and suppresses TLR3 ligand-promoted invasion in cholangiocarcinoma[J]. Cell Communication and Signaling, 2020, 18(1): 161.
[5] Alcala A, Osborne B, Allen B, et al. Toll-like receptors in the mechanism of tributyltin-induced production of pro-inflammatory cytokines, IL-1β and IL-6[J]. Toxicology, 2022, 472: 153177.
[6] Mukherjee R, Bhattacharya A, Bojkova D, et al. Famotidine inhibits toll-like receptor 3-mediated inflammatory signaling in SARS-CoV-2 infection[J]. Journal of Biological Chemistry, 2021, 297(2).
[7] Neu C, Thiele Y, Horr F, et al. DAMPs released from proinflammatory macrophages induce inflammation in cardiomyocytes via activation of TLR4 and TNFR[J]. International journal of molecular sciences, 2022, 23(24): 15522.
[8] Sardana S, Singh K P, Saminathan M, et al. Effect of inhibition of Toll-like receptor 3 signaling on pathogenesis of rabies virus in mouse model[J]. Acta Tropica, 2022, 234: 106589.
CU CPT 4a 是一种有效的 Toll 样受体 3（TLR3）抑制剂，IC50值为3.44μM[1]。CU CPT 4a通过抑制TLR3/dsRNA复合物介导的下游信号通路，进而干扰素和促炎细胞因子（TNF-α、IL-1β和IL-6）的产生[2]。CU CPT 4a已广泛应用于动物模型中，以调节 TLR3 介导的炎症反应[3]。
在体外，用40μM的CU CPT 4a预处理KKU213细胞1小时，能显著抑制由2.5μg/ml Poly(I:C)（处理 12 小时）诱导的细胞侵袭[4]。用20µM的CU CPT 4a处理人外周血单核细胞1小时，可显著抑制Tributyltin (TBT)（25nM）诱导的IL-1β和IL-6 产生[5]。在SARS-CoV-2感染的Caco2细胞中，使用10µM的CU CPT 4a处理24小时，能够消除组胺对TBK1/IRF3信号通路的激活作用[6]。用40μM的CU CPT 4a处理小鼠心肌细胞24小时，降低了Caspase-3/7的活化水平，未减弱LPS刺激的细胞凋亡[7]。
在体内，通过腹腔注射CU CPT 4a（30μg/10μl；5天内注射3次）治疗Street rabies virus (SRABV) 感染的小鼠，能显著延缓疾病进展、减轻临床症状和病理损伤程度、降低病毒载量、显著减少内基氏体形成，并延长存活时间[8]。