干扰素基因刺激因子(STING)及其激动剂的研究进展

Research advances on stimulator of interferon genes(STING)and its agonists

干扰素基因刺激因子(stimulator of interferon genes,STING)作为参与固有免疫反应的关键信号转导分子,被来自病原体和宿主的胞质DNA触发,在诱导Ⅰ型干扰素和促炎性细胞因子分泌、防御病毒及胞内细菌感染、调节体内自发性抗肿瘤免疫反应产生过程中发挥重要功能。STING激动剂能够有效治疗病原体感染和癌症。近10年来,对STING及其激动剂的研究发展迅速。本文从STING的结构和激活、cGAS-STING通路的机制等方面概述了STING的最新研究进展,尤其对STING激动剂进行了概述,重点分析了STING与其激动剂复合物的晶体结构以及STING激动剂的构效关系,并总结了研发STING激动剂所面临的严峻挑战,试图为设计和发现小分子STING激动剂提供思路。

As a key signal transduction molecule involved in the innate immune response,stimulator of interferon genes(STING)is triggered by cytosolic DNA from pathogen and host origins,and plays an important role in inducing the secretion of type I interferons and proinflammatory cytokines,thereby defending against viral and intracellular bacterial infections and regulating the production of spontaneous antitumor immune responses in vivo.Thus,STING agonists have shown useful therapeutic effects for pathogen infection and cancer.In the past decade research on STING and its agonists has progressed rapidly.Here,we summarize recent advances in the structure and activation of STING and the mechanism of the cGAS-STING pathway.In particular,we review research advances of STING agonists,analyze the crystal structure of STING in complex with its agonists and the structureactivity relationship of STING agonists,and summarize the strong challenges of developing STING agonists.