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STING inhibitors target the cyclic dinucleotide binding pocket [Immunology and Inflammation]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.412 ) Pub Date : 2021-06-15 , DOI: 10.1073/pnas.2105465118
Ze Hong, Jiahao Mei, Chenhui Li, Guohui Bai, Munire Maimaiti, Haiyang Hu, Wenying Yu, Li Sun, Lele Zhang, Dan Cheng, Yixian Liao, Senlin Li, Yanping You, Hongbin Sun, Jing Huang, Xing Liu, Judy Lieberman, Chen Wang

Cytosolic DNA activates cGAS (cytosolic DNA sensor cyclic AMP-GMP synthase)-STING (stimulator of interferon genes) signaling, which triggers interferon and inflammatory responses that help defend against microbial infection and cancer. However, aberrant cytosolic self-DNA in Aicardi–Goutière’s syndrome and constituently active gain-of-function mutations in STING in STING-associated vasculopathy with onset in infancy (SAVI) patients lead to excessive type I interferons and proinflammatory cytokines, which cause difficult-to-treat and sometimes fatal autoimmune disease. Here, in silico docking identified a potent STING antagonist SN-011 that binds with higher affinity to the cyclic dinucleotide (CDN)-binding pocket of STING than endogenous 2′3′-cGAMP. SN-011 locks STING in an open inactive conformation, which inhibits interferon and inflammatory cytokine induction activated by 2′3′-cGAMP, herpes simplex virus type 1 infection, Trex1 deficiency, overexpression of cGAS-STING, or SAVI STING mutants. In Trex1−/− mice, SN-011 was well tolerated, strongly inhibited hallmarks of inflammation and autoimmunity disease, and prevented death. Thus, a specific STING inhibitor that binds to the STING CDN-binding pocket is a promising lead compound for STING-driven disease.



中文翻译:

STING 抑制剂靶向环状二核苷酸结合口袋 [免疫学和炎症]

细胞质 DNA 激活 cGAS(细胞质 DNA 传感器环 AMP-GMP 合酶)-STING(干扰素基因刺激剂)信号,从而触发干扰素和炎症反应,帮助抵御微生物感染和癌症。然而,Aicardi-Goutière 综合征中的异常胞质自体 DNA 和婴儿期发病的 STING 相关血管病 (SAVI) 患者中 STING 的组成性活性功能获得性突变导致过量的 I 型干扰素和促炎细胞因子,从而导致困难治疗有时是致命的自身免疫性疾病。在这里,计算机对接鉴定了一种有效的 STING 拮抗剂 SN-011,与内源性 2'3'-cGAMP 相比,它与 STING 的环状二核苷酸 (CDN) 结合口袋的结合亲和力更高。SN-011 将 STING 锁定在开放的非活动构象中,Trex1缺陷、cGAS-STING 过表达或 SAVI STING 突变体。在Trex1 -/-小鼠中,SN-011 具有良好的耐受性,强烈抑制炎症和自身免疫性疾病的特征,并防止死亡。因此,与 STING CDN 结合口袋结合的特定 STING 抑制剂是治疗 STING 驱动疾病的有前途的先导化合物。

更新日期:2021-06-08
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