Discovery and characterization of a novel cGAS covalent inhibitor for the treatment of inflammatory bowel disease
Discovery and characterization of a novel cGAS covalent inhibitor for the treatment of inflammatory bowel disease
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用于治疗炎症性肠病的新型 cGAS 共价抑制剂的发现和表征
DOI：
10.1038/s41401-022-01002-5
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发表时间：
2022-10
影响因子：
8.2
通讯作者：
Ming-yue Zheng
中科院分区：
文献类型：
--
作者：
Jia Song;Rui-rui Yang;Jie Chang;Ya-dan Liu;Cheng-hao Lu;Li-fan Chen;Hao Guo;Ying-hui Zhang;Zi-sheng Fan;Jing-yi Zhou;Gui-zhen Zhou;Ke-ke Zhang;Xiao-min Luo;Kai-xian Chen;Hua-liang Jiang;Su-lin Zhang;Ming-yue Zheng
环GMP-AMP合酶（cGAS）是一种细胞质DNA传感器，作为核苷酸转移酶，催化ATP和GTP形成环GMP-AMP（cGAMP），在先天免疫中起关键作用。cGAS-STING信号传导的过度活化有助于炎症反应过度。因此，cGAS被认为是治疗炎性疾病的有希望的靶标。在本文中，我们报告了通过焦磷酸酶（PPiase）偶联活性测定发现和鉴定几种新型cGAS抑制剂。在这些抑制剂中，1-（1-苯基-3，4-二氢-1H-吡咯并[1，2-a]吡嗪-2-基）丙-2-炔-1-酮（化合物3）在细胞水平上显示出最高的效力和选择性。化合物3表现出比RU. 521更好的抑制活性和途径选择性，RU. 521是具有体外和体内抗炎作用的选择性cGAS抑制剂。热稳定性分析、核磁共振和等温滴定量热分析证实化合物3直接结合cGAS蛋白。质谱和突变分析显示化合物3与cGAS的Cys 419共价结合。值得注意的是，化合物3在葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎模型中表现出有希望的治疗功效。这些结果共同表明，化合物3将有助于理解cGAS的生物学功能，并有可能进一步开发用于炎症性疾病治疗。
Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, acts as a nucleotidyl transferase that catalyzes ATP and GTP to form cyclic GMP-AMP (cGAMP) and plays a critical role in innate immunity. Hyperactivation of cGAS-STING signaling contributes to hyperinflammatory responses. Therefore, cGAS is considered a promising target for the treatment of inflammatory diseases. Herein, we report the discovery and identification of several novel types of cGAS inhibitors by pyrophosphatase (PPiase)-coupled activity assays. Among these inhibitors, 1-(1-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-yl)prop-2-yn-1-one (compound3) displayed the highest potency and selectivity at the cellular level. Compound3exhibited better inhibitory activity and pathway selectivity than RU.521, which is a selective cGAS inhibitor with anti-inflammatory effects in vitro and in vivo. Thermostability analysis, nuclear magnetic resonance and isothermal titration calorimetry assays confirmed that compound3directly binds to the cGAS protein. Mass spectrometry and mutation analysis revealed that compound3covalently binds to Cys419 of cGAS. Notably, compound3demonstrated promising therapeutic efficacy in a dextran sulfate sodium (DSS)-induced mouse colitis model. These results collectively suggest that compound3will be useful for understanding the biological function of cGAS and has the potential to be further developed for inflammatory disease therapies.
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影响因子：
8.8
作者：
Zhang X;Wu J;Du F;Xu H;Sun L;Chen Z;Brautigam CA;Zhang X;Chen ZJ
通讯作者：
Chen ZJ
影响因子：
9
作者：
Zhao F;Zheng T;Gong W;Wu J;Xie H;Li W;Zhang R;Liu P;Liu J;Wu X;Zhao Y;Ren J
通讯作者：
Ren J
影响因子：
64.8
作者：
通讯作者：
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影响因子：
8.8
作者：
Ahn J;Son S;Oliveira SC;Barber GN
通讯作者：
Barber GN
影响因子：
7.3
作者：
Jing Tan;B. Wu;Tingting Chen;Chen Fan;Jiannan Zhao;Chaodong Xiong;Chun-lan Feng;Ruoxuan Xiao;C. Ding;Wei Tang;Ao Zhang
通讯作者：
Jing Tan;B. Wu;Tingting Chen;Chen Fan;Jiannan Zhao;Chaodong Xiong;Chun-lan Feng;Ruoxuan Xiao;C. Ding;Wei Tang;Ao Zhang