刺
干扰素基因刺激剂
化学
配体(生物化学)
干扰素
药理学
立体化学
生物化学
生物
受体
先天免疫系统
免疫学
工程类
航空航天工程
作者
Yurui Xu,Wei Li,Xinyuan Zhou,Ya Gao,Likang Ding,Lei Xu,Xianxian Mao,Anwei Zhou,Xiaojian Wang,Xinghai Ning
出处
期刊:Langmuir
[American Chemical Society]
日期:2022-11-10
卷期号:38 (46): 14185-14191
标识
DOI:10.1021/acs.langmuir.2c02199
摘要
Although small-molecule agonists of stimulator of interferon genes (STING) show significance in activating the immune system, the dynamic process involved in ligands activating STING remains unclear. Herein, we developed a biochemical strategy, integrating computer simulation and a biochemical engineering approach, to reveal the interaction mechanism between STING and 5,6-dimethylxanthenone-4-acetic acid (DMXAA), an agonist that activates the TANK binding kinase 1-interferon regulatory factor 3 signaling pathway. Specifically, inspired by an analysis of the STING-DMXAA crystal structure, we designed and synthesized DMXAA derivatives to investigate the STING-DMXAA binding model. We identified that the carboxyl moiety of DMXAA was a major pharmacophore responsive to STING activation. In particular, the loss of hydrogen bond interaction between the carboxylic acid of DMXAA and the side chain Thr262 of STING led to STING inhibition. DMXAA N-methyl amide derivative (DNHM) exhibited good inhibitor activity, inhibited STING-mediated interferon production in vitro and in vivo, and effectively attenuated STING-associated inflammatory diseases. Therefore, we provide a new insight into STING-ligand interactions, which may improve the understanding of STING biology.
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