STING inhibitors target the cyclic dinucleotide binding pocket.
Ze HongJiahao MeiChenhui LiGuohui BaiMunire MaimaitiHaiyang HuWenying YuLi SunLele ZhangDan ChengYixian LiaoSenlin LiYanping YouHongbin SunJing HuangXing LiuJudy LiebermanChen WangPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
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.
Keyphrases
- oxidative stress
- dendritic cells
- cell proliferation
- cell free
- multiple sclerosis
- adipose tissue
- single molecule
- physical activity
- newly diagnosed
- transcription factor
- chronic kidney disease
- gene expression
- young adults
- binding protein
- molecular dynamics
- immune response
- end stage renal disease
- skeletal muscle
- molecular dynamics simulations
- prognostic factors
- insulin resistance
- escherichia coli
- protein kinase
- weight loss
- smoking cessation
- replacement therapy
- childhood cancer
- wild type