STING inhibitors target the cyclic dinucleotide binding pocket
Open Access
- 7 June 2021
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 118 (24)
- https://doi.org/10.1073/pnas.2105465118
Abstract
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.Keywords
Funding Information
- National Natural Science Foundation of China (31730018)
- National Natural Science Foundation of China (81672029)
- National Natural Science Foundation of China (3173000227)
- National Natural Science Foundation of China (31470428)
- National Key R&D Program of China (2016YFA0501800)
- National Basic Research Program of China (2013CB127505)
- Jiangsu Innovative and Entrepreneurial Talents Program, the National New Drug Innovation Major Project of China (2017ZX09309027)
- Fund of Chinese Academy of Sciences (XDA09030301-4)
- China Postdoctoral Research Program (2019TQ0356)
- National Natural Science Foundation of China for the Youth (31800724)
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