Molecular action mechanisms of two novel and selective calcium release-activated calcium channel antagonists.
Molecular action mechanisms of two novel and selective calcium release-activated calcium channel antagonists.
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DOI：
10.1016/j.ijbiomac.2023.126937
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发表时间：
2023-09
影响因子：
8.2
通讯作者：
Xiangjin Kong;Feifan Wang;Yan Chen;Xinyao Liang;Yuan Yin;H. Liu;Guoqing Luo;Yinping Li
中科院分区：
文献类型：
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作者：
Xiangjin Kong;Feifan Wang;Yan Chen;Xinyao Liang;Yuan Yin;H. Liu;Guoqing Luo;Yinping Li
由STIM 1和Orai 1组成的原型钙释放激活钙（CRAC）通道是治疗自身免疫性疾病的广受欢迎的药物靶标。在此，我们鉴定了两种新型的选择性CRAC通道抑制剂，吲哚样化合物C63368和含吡唑核的化合物C79413，它们以低微摩尔IC50有效且可逆地抑制CRAC通道，并保留各种脱靶离子通道。这两种化合物不抑制STIM 1激活或其与Orai 1的偶联，也不影响通道的钙依赖性快速失活。相反，它们直接作用于Orai1蛋白，通道的孔几何形状深刻地影响了它们的效力。在体外，C63368和C79413有效地抑制Jurkat细胞增殖和人T淋巴细胞中细胞因子的产生。小鼠灌胃给予C63368和C79413在自身免疫性疾病的银屑病和结肠炎动物模型中产生了巨大的治疗获益，减少了血清细胞因子的产生并显著缓解了病理症状。值得注意的是，这项研究首次深入了解了吲哚样CRAC通道拮抗剂的表征和机制研究。总之，这两种高选择性CRAC通道拮抗剂的鉴定，加上其作用机制的阐明，不仅提供了有价值的模板分子，而且为靶向CRAC通道的药物开发提供了深刻的见解。
The prototypical calcium release-activated calcium (CRAC) channel, composed of STIM1 and Orai1, is a sought-after drug target for treating autoimmune disorders. Herein, we identified two novel and selective CRAC channel inhibitors, the indole-like compound C63368 and pyrazole core-containing compound C79413, potently and reversibly inhibiting the CRAC channel with low micromolar IC50s and sparing various off-target ion channels. These two compounds did not inhibit STIM1 activation or its coupling with Orai1, nor did they affect the channel's calcium-dependent fast inactivation. Instead, they directly acted on the Orai1 protein, with the channel's pore geometry profoundly affecting their potencies. In vitro, C63368 and C79413 effectively inhibited Jurkat cell proliferation and cytokines production in human T lymphocytes. Intragastric administration of C63368 and C79413 to mice yielded great therapeutic benefits in psoriasis and colitis animal models of autoimmune disorders, reducing serum cytokines production and significantly relieving pathological symptoms. It's worth noting, that this study provided the first insight into the characterization and mechanistic investigation of an indole-like CRAC channel antagonist. Altogether, the identification of these two highly selective CRAC channel antagonists, coupled with the elucidation of their action mechanisms, not only provides valuable template molecules but also offers profound insights for drug development targeting the CRAC channel.