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  3. Targeting STING oligomerization with licochalcone D ameliorates STING-driven inflammatory diseases

Targeting STING oligomerization with licochalcone D ameliorates STING-driven inflammatory diseases

  • Sci China Life Sci. 2024 Aug 22. doi: 10.1007/s11427-024-2703-6.
Yinghui Zhang # 1 2,  Yadan Liu # 1 3,  Bing Jiang # 3,  Lifan Chen 1 2,  Jie Hu 3,  Buying Niu 1 2,  Jie Chang 1,  Zisheng Fan 1 4,  Jingyi Zhou 1 5,  Yajie Wang 2 6,  Dan Teng 1 2,  Ning Ma 2 6,  Xiaofeng Wang 2 6,  Ruirui Yang 7 8,  Mingyue Zheng 9 10 11 12 13 14 15,  Sulin Zhang 16 17
Affiliations

Affiliations

  • 1 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 4 Shanghai Institute for Advanced Immunochemical Studies, and School of Life Science and Technology, Shanghai Tech University, Shanghai, 200031, China.
  • 5 School of Physical Science and Technology, ShanghaiTech University, Shanghai, 200031, China.
  • 6 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
  • 7 University of Chinese Academy of Sciences, Beijing, 100049, China. yangruirui@simm.ac.cn.
  • 8 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. yangruirui@simm.ac.cn.
  • 9 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. myzheng@simm.ac.cn.
  • 10 University of Chinese Academy of Sciences, Beijing, 100049, China. myzheng@simm.ac.cn.
  • 11 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China. myzheng@simm.ac.cn.
  • 12 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. myzheng@simm.ac.cn.
  • 13 Shanghai Institute for Advanced Immunochemical Studies, and School of Life Science and Technology, Shanghai Tech University, Shanghai, 200031, China. myzheng@simm.ac.cn.
  • 14 School of Physical Science and Technology, ShanghaiTech University, Shanghai, 200031, China. myzheng@simm.ac.cn.
  • 15 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, China. myzheng@simm.ac.cn.
  • 16 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. slzhang@simm.ac.cn.
  • 17 University of Chinese Academy of Sciences, Beijing, 100049, China. slzhang@simm.ac.cn.
  • # Contributed equally.
PMID: 39190126 DOI: 10.1007/s11427-024-2703-6
Abstract

The development of STING inhibitors for the treatment of STING-related inflammatory diseases continues to encounter significant challenges. The activation of STING is a multi-step process that includes binding with cGAMP, self-oligomerization, and translocation from the endoplasmic reticulum to the Golgi apparatus, ultimately inducing the expression of IRF3 and NF-κB-mediated interferons and inflammatory cytokines. It has been demonstrated that disruption of any of these steps can effectively inhibit STING activation. Traditional structure-based drug screening methodologies generally focus on specific binding sites. In this study, a TransformerCPI model based on protein primary sequences and independent of binding sites is employed to identify compounds capable of binding to the STING protein. The natural product Licochalcone D (LicoD) is identified as a potent and selective STING Inhibitor. LicoD does not bind to the classical ligand-binding pocket; instead, it covalently modifies the Cys148 residue of STING. This modification inhibits STING oligomerization, consequently suppressing the recruitment of TBK1 and the nuclear translocation of IRF3 and NF-κB. LicoD treatment ameliorates the inflammatory phenotype in Trex1-1- mice and inhibits the progression of DSS-induced colitis and AOM/DSS-induced colitis-associated colon Cancer (CAC). In summary, this study reveals the potential of LicoD in treating STING-driven inflammatory diseases. It also demonstrates the utility of the TransformerCPI model in discovering allosteric compounds beyond the conventional binding pockets.

Keywords

Licochalcone D; STING inhibitor; TransformerCPI model; cGAS-STING signaling; inflammatory diseases.

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