Physiopathogénèse et Traitements des Maladies du Foie, Université Paris-Saclay, Rue des Adeles, 91405 Orsay, France.
INSERM U1193, Rue des Adeles, 91405 Orsay, France.
Int J Mol Sci. 2020 Dec 21;21(24):9777. doi: 10.3390/ijms21249777.
The store-operated calcium entry, better known as SOCE, forms the main Ca influx pathway in non-excitable cells, especially in leukocytes, where it is required for cell activation and the immune response. During the past decades, several inhibitors were developed, but they lack specificity or efficacy. From the non-specific SOCE inhibitor 2-aminoethyl diphenylborinate (2-APB), we synthetized 16 new analogues by replacing/modifying the phenyl groups. Among them, our compound P11 showed the best inhibitory capacity with a ≈ 75 nM. Furthermore, below 1 µM, P11 was devoid of any inhibitory activity on the two other main cellular targets of 2-APB, the IP receptors, and the SERCA pumps. Interestingly, Jurkat T cells secrete interleukin-2 under phytohemagglutinin stimulation but undergo cell death and stop IL-2 synthesis when stimulated in the presence of increasing P11 concentrations. Thus, P11 could represent the first member of a new and potent family of immunosuppressors.
钙库操纵性钙内流，又称 SOCE，是构成非兴奋细胞（尤其是白细胞）内主要钙离子内流途径的一部分，其对于细胞激活和免疫反应是必需的。在过去几十年中，已经开发出了几种抑制剂，但它们缺乏特异性或疗效。我们从非特异性 SOCE 抑制剂 2-氨基乙基二苯硼酸盐（2-APB）出发，通过替换/修饰苯基基团合成了 16 种新的类似物。其中，我们的化合物 P11 表现出最佳的抑制能力，其 IC50 约为 75 nM。此外，在低于 1 μM 的浓度下，P11 对 2-APB 的另外两个主要细胞靶标，即 IP 受体和 SERCA 泵，没有任何抑制活性。有趣的是，植物血球凝集素刺激下的 Jurkat T 细胞会分泌白细胞介素-2，但当存在浓度逐渐增加的 P11 时，细胞会死亡并停止白细胞介素-2的合成。因此，P11 可能代表了一种新型强效免疫抑制剂家族的第一个成员。
