STING inhibitors target the cyclic dinucleotide binding pocket

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 24; p. 1
• 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; Infections; Inflammation; Interferon; Lead compounds; Microorganisms; Mutation; Stimulators; Vascular diseases; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2105465118

Significance cGAS (cytosolic DNA sensor cyclic AMP-GMP synthase)-STING (stimulator of interferon genes) signaling is critical for sensing cytosolic DNA to initiate host immune responses against invading pathogens and cancer. However, inappropriate activation of STING signaling causes severe and often fatal autoimmune or autoinflammatory diseases. Hence, STING is an attractive drug target for the treatment of STING-driven autoimmune and inflammatory disorders. Therefore, there is a need to identify lead compounds that effectively inhibit human STING for further drug development. Here, we identified and characterized a STING-specific inhibitor SN-011 with high efficiency, specificity, and safety, paving the way for therapeutically manipulating STING-mediated clinical diseases. 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.