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Discovery and characterization of a novel cGAS covalent inhibitor for the treatment of inflammatory bowel disease

文献类型：期刊论文

作者Song, Jia5,6; Yang, Rui-rui2,3,4,5; Chang, Jie5; Liu, Ya-dan1; Lu, Cheng-hao1; Chen, Li-fan4,5; Guo, Hao4,5; Zhang, Ying-hui4,5; Fan, Zi-sheng1,5; Zhou, Jing-yi1,5
刊名ACTA PHARMACOLOGICA SINICA
出版日期2022-10-13
页码10
关键词cyclic GMP-AMP synthase covalent inhibitor inflammatory bowel disease high-throughput screening
ISSN号1671-4083
DOI10.1038/s41401-022-01002-5
通讯作者Jiang, Hua-liang(hljiang@simm.ac.cn) ; Zhang, Su-lin(slzhang@simm.ac.cn) ; Zheng, Ming-yue(myzheng@simm.ac.cn)
英文摘要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 (PP(i)ase)-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 (compound 3) displayed the highest potency and selectivity at the cellular level. Compound 3 exhibited 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 compound 3 directly binds to the cGAS protein. Mass spectrometry and mutation analysis revealed that compound 3 covalently binds to Cys419 of cGAS. Notably, compound 3 demonstrated promising therapeutic efficacy in a dextran sulfate sodium (DSS)-induced mouse colitis model. These results collectively suggest that compound 3 will be useful for understanding the biological function of cGAS and has the potential to be further developed for inflammatory disease therapies.
WOS关键词CYCLIC GMP-AMP ; DNA SENSOR ; ACTIVATION ; SYNTHASE ; 2ND-MESSENGER
资助项目National Natural Science Foundation of China[T2225002] ; National Natural Science Foundation of China[82273855] ; National Natural Science Foundation of China[81903639] ; National Natural Science Foundation of China[LG202102-01-02] ; National Natural Science Foundation of China[LG-QS-202204-01] ; Shanghai Municipal Science and Technology Major Project ; Natural Science Foundation of Shanghai[22ZR1474300]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000867545400005
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/302739]  
专题新药研究国家重点实验室
通讯作者Jiang, Hua-liang; Zhang, Su-lin; Zheng, Ming-yue
作者单位1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
2.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China
3.Shanghai Tech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 200031, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
6.Univ Sci & Technol China, Affiliated Hosp USTC 1, Div Life Sci & Med, Hefei 230001, Peoples R China
推荐引用方式
GB/T 7714		 Song, Jia,Yang, Rui-rui,Chang, Jie,et al. Discovery and characterization of a novel cGAS covalent inhibitor for the treatment of inflammatory bowel disease[J]. ACTA PHARMACOLOGICA SINICA,2022:10.
APA Song, Jia.,Yang, Rui-rui.,Chang, Jie.,Liu, Ya-dan.,Lu, Cheng-hao.,...&Zheng, Ming-yue.(2022).Discovery and characterization of a novel cGAS covalent inhibitor for the treatment of inflammatory bowel disease.ACTA PHARMACOLOGICA SINICA,10.
MLA Song, Jia,et al."Discovery and characterization of a novel cGAS covalent inhibitor for the treatment of inflammatory bowel disease".ACTA PHARMACOLOGICA SINICA (2022):10.

入库方式： OAI收割

来源：上海药物研究所

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