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.
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Acknowledgement
We thank the staff members of the Large-scale Protein Preparation System at the National Facility for Protein Science in Shanghai (NFPS), Shanghai Advanced Research Institute, Chinese Academy of Science, China for providing technical support and assistance in data collection and analysis. We gratefully acknowledge financial support from National Natural Science Foundation of China (T2225002, 82273855, 82304379, 81903639), National Key Research and Development Program of China (2022YFC3400504), the Youth Innovation Promotion Association CAS (2023296), the SIMM-SHUTCM Traditional Chinese Medicine Innovation Joint Research Program (E2G805H), the open fund of state key laboratory of Pharmaceutical Biotechnology, Nanjing University, China (KF-202301), the Natural Science Foundation of Shanghai (22ZR1474300), Lingang Laboratory (LG202102-01-02, LG-QS-202204-01), and Young Elite Scientists Sponsorship Program by CAST (2023QNRC001)
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The author(s) declare that they have no conflict of Interest. All animal experiments were carried out in strict accordance with the guidelines and regulations of the Institutional Animal Care and Use Committees (IACUC) of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences.
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Zhang, Y., Liu, Y., Jiang, B. et al. Targeting STING oligomerization with licochalcone D ameliorates STING-driven inflammatory diseases. Sci. China Life Sci. (2024). https://doi.org/10.1007/s11427-024-2703-6
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DOI: https://doi.org/10.1007/s11427-024-2703-6