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

Science China Life Sciences 2024年第12期67卷 2664-2677页

作者： Yinghui Zhang Yadan Liu Bing Jiang Lifan Chen Jie Hu Buying Niu Jie Chang Zisheng Fan Jingyi Zhou Yajie Wang Dan Teng Ning Ma Xiaofeng Wang Ruirui Yang Mingyue Zheng Sulin Zhang Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences University of Chinese Academy of Sciences School of Chinese Materia Medica Nanjing University of Chinese Medicine Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology Shanghai Tech University School of Physical Science and Technology Shanghai Tech University School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences State Key Laboratory of Pharmaceutical Biotechnology Nanjing University

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 c GAMP, 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 Transformer CPI 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(Lico D) is identified as a potent and selective sting inhibitor. Lico D does not bind to the classical ligandbinding 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. Lico D treatment ameliorates the inflammatory phenotype in Trex1-/-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 Lico D in treating sting-driven inflammatory diseases. It also demonstrates the utility of the Transformer CPI model in discovering allosteric compounds beyond the conventional binding pockets.

关键词： cgas-sting signaling sting inhibitor TransformerCPI model Licochalcone D inflammatory diseases

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