2. Academic Validation
  3. STING inhibitors target the cyclic dinucleotide binding pocket

STING inhibitors target the cyclic dinucleotide binding pocket

  • Proc Natl Acad Sci U S A. 2021 Jun 15;118(24):e2105465118. doi: 10.1073/pnas.2105465118.
Ze Hong 1,  Jiahao Mei 1,  Chenhui Li 1,  Guohui Bai 2,  Munire Maimaiti 1,  Haiyang Hu 1,  Wenying Yu 3,  Li Sun 4,  Lele Zhang 5,  Dan Cheng 1,  Yixian Liao 3,  Senlin Li 5,  Yanping You 4,  Hongbin Sun 3,  Jing Huang 2,  Xing Liu 6,  Judy Lieberman 7,  Chen Wang 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, 211198 Nanjing, China.
  • 2 Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China.
  • 3 State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 211198 Nanjing, China.
  • 4 State Key Laboratory of Natural Medicines, Center for Drug Discovery, China Pharmaceutical University, 211198 Nanjing, China.
  • 5 State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China.
  • 6 Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, 200031 Shanghai, China.
  • 7 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115 judy.lieberman@childrens.harvard.edu cwang1971@cpu.edu.cn.
  • 8 State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, 211198 Nanjing, China; judy.lieberman@childrens.harvard.edu cwang1971@cpu.edu.cn.
PMID: 34099558 DOI: 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

Aicardi–Goutières syndrome; SAVI; STING; antagonist; type I interferons.

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