Novel DCPIB analogs as dual inhibitors of VRAC/TREK1 channels reduced cGAS-STING mediated interferon responses.
Novel DCPIB analogs as dual inhibitors of VRAC/TREK1 channels reduced cGAS-STING mediated interferon responses.
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DOI：
10.1016/j.bcp.2022.114988
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发表时间：
2022-03
影响因子：
5.8
通讯作者：
Yuanxing Zhi;Jin Liu;Peihua Kuang;Xin Zhang;Ziwei Xu;Yanshan Chen;Xiuling Lin;Xiaoyan Wu;Pingzheng Zhou;Jianjun Chen
中科院分区：
文献类型：
--
作者：
Yuanxing Zhi;Jin Liu;Peihua Kuang;Xin Zhang;Ziwei Xu;Yanshan Chen;Xiuling Lin;Xiaoyan Wu;Pingzheng Zhou;Jianjun Chen
环 GMP-AMP 合酶 (cGAS) 感知胞质 DNA 并催化 2'3'-环 GMP-AMP (cGAMP) 的形成，进而触发干扰素 (IFN) 的产生。 cGAS 的不当激活和 cGAMP 的产生与多种自身免疫性疾病有关。最近已证明体积调节阴离子通道 (VRAC) 可以渗透 cGAMP，从而使该通道对于 cGAS-cGAMP-STING 轴的激活至关重要。 DCPIB 是 VRAC 通道的一种重要抑制剂，最近有报道称还能显着激活 TREK1 通道。在本研究中，我们设计并合成了一系列新型DCPIB衍生物，并研究了它们对VRAC/TREK1通道的潜在调节作用。我们的结果表明，compound6u 是 VRAC/TREK1 通道的双重抑制剂，IC50 分别为 7.11 ± 0.94 μM 和 4.43 ± 0.90 μM。最重要的是，我们的数据表明，当涉及 1 型单纯疱疹病毒 (HSV1) 感染时，通过抑制 cGAS-cGAMP-STING 途径，以浓度依赖性方式损害干扰素的产生，而没有任何细胞毒性。综上所述，我们的研究不仅发现了一种对VRAC/TREK1通道具有双重抑制作用的新型DCPIB类似物，而且为设计和开发新型强效VRAC抑制剂提供了新策略，有利于cGAS-STING相关自身免疫和炎症性疾病的治疗。
The enzyme cyclic GMP-AMP synthase (cGAS) senses cytosolic DNA and catalyzes the formation of 2′3′-cyclic-GMP-AMP (cGAMP), which in turn triggers interferon (IFN) production. Inappropriate activation of cGAS and production of cGAMP have been linked to a diversity of autoimmune diseases. The volume-regulated anion channels (VRACs) have been recently demonstrated to permeate cGAMP, thus making the channel essential for the activation of the cGAS-cGAMP-STING axis. DCPIB, a prominent inhibitor of VRAC channel, has been recently reported to also significantly activate TREK1 channel. Herein, in this study, we have designed and synthesized a series of novel DCPIB derivatives and investigated their potential regulatory effects on VRAC/TREK1 channels. Our results manifested that compound6uwas a dual inhibitor of VRAC/TREK1 channels with IC50s of 7.11 ± 0.94 μM and 4.43 ± 0.90 μM, respectively. On top of that, our data demonstrated that6uimpaired interferon production in a concentration-dependently manner by dampening cGAS-cGAMP-STING pathway without any cytotoxicity when it comes to herpes simplex virus type 1 (HSV1) infection. To sum up, our study not only discovered a novel DCPIB analog with dual inhibitory effects on VRAC/TREK1 channels but also provided a new strategy for the design and development of newly potent VRAC inhibitors, which benefits the treatment of cGAS-STING related autoimmune and inflammatory diseases.