The calcineurin/nuclear factor of activated T cell (CN/NFAT) signaling pathway plays a critical role in the immune response. Therefore, inhibition of the CN/NFAT pathway is an important target for inflammatory disease. The conserved PXIXIT and LXVP motifs of CN substrates and targeting proteins have been recognized. Based on the affinity ability and inhibitory effect of these docking sequences on CN, we designed a bioactive peptide (named pep3) against the CN/NFAT interaction, which has two binding sites derived from the RCAN1-PXIXIT motif and the NFATc1-LXVP motif. The shortest linker between the two binding sites in pep3 is derived from A238L, a physiological binding partner of CN. Microscale thermophoresis revealed that pep3 has two docking sites on CN. Pep3 also has the most potent inhibitory effect on CN. It is suggested that pep3 contains an NFATc1-LXVP-substrate recognition motif and RCAN1-PXIXIT-mediated anchoring to CN. Expression of this peptide significantly suppresses CN/NFAT signaling. Cell-permeable 11-arginine-modified pep3 (11R-pep3) blocks the NFAT downstream signaling pathway. Intranasal administration of the 11R-pep3 peptide inhibits airway inflammation in an ovalbumin-induced asthma model. Our results suggest that pep3 is promising as an immunosuppressive agent and can be used in topical remedies.

中文翻译：

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一种新型肽通过阻断NFAT与钙调神经磷酸酶的两点相互作用而发挥有效的免疫抑制作用。

活化的T细胞（CN / NFAT）信号通路的钙调神经磷酸酶/核因子在免疫应答中起关键作用。因此，抑制CN / NFAT途径是炎性疾病的重要靶标。CN底物和靶向蛋白的保守PXIXIT和LXVP基序已被识别。基于这些对接序列对CN的亲和力和抑制作用，我们设计了一种抗CN / NFAT相互作用的生物活性肽（名为pep3），该肽具有两个源自RCAN1-PXIXIT基序和NFATc1-LXVP基序的结合位点。pep3中两个结合位点之间的最短接头来自CN的生理结合伴侣A238L。微型热泳显示，pep3在CN上有两个停靠位点。Pep3对CN的抑制作用也最强。建议pep3包含一个NFATc1-LXVP-底物识别基序和RCAN1-PXIXIT介导的对CN的锚定。该肽的表达显着抑制CN / NFAT信号传导。细胞可渗透的11-精氨酸修饰的pep3（11R-pep3）阻断NFAT下游信号传导途径。鼻内施用11R-pep3肽可抑制卵清蛋白诱导的哮喘模型中的气道炎症。我们的结果表明，pep3有希望作为一种免疫抑制剂，并可用于局部治疗。鼻内施用11R-pep3肽可抑制卵清蛋白诱导的哮喘模型中的气道炎症。我们的结果表明，pep3有希望作为一种免疫抑制剂，可用于局部治疗。鼻内施用11R-pep3肽可抑制卵清蛋白诱导的哮喘模型中的气道炎症。我们的结果表明，pep3有希望作为一种免疫抑制剂，并可用于局部治疗。