STING inhibitors target the cyclic dinucleotide binding pocket

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 24; pp. 1 - 10
• Main Authors: Hong, Ze, Mei, Jiahao, Li, Chenhui, Bai, Guohui, Maimaiti, Munire, Hu, Haiyang, Yu, Wenying, Sun, Li, Zhang, Lele, Cheng, Dan, Liao, Yixian, Li, Senlin, You, Yanping, Sun, Hongbin, Huang, Jing, Liu, Xing, Lieberman, Judy, Wang, Chen
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 15.06.2021
• Subjects: Autoimmune diseases; Autoimmunity; Binding; Biological Sciences; Conformation; Cyclic AMP; Cytokines; Deoxyribonucleic acid; DNA; GMP synthase; Herpes simplex; Inflammation; Interferon; Lead compounds; Microorganisms; Mutation; Stimulators; Vascular diseases
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2105465118

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.