Zhang Yinghui, Liu Yadan, Jiang Bing, Chen Lifan, Hu Jie, Niu Buying, Chang Jie, Fan Zisheng, Zhou Jingyi, Wang Yajie, Teng Dan, Ma Ning, Wang Xiaofeng, Yang Ruirui, Zheng Mingyue, Zhang Sulin
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Sci China Life Sci. 2024 Dec;67(12):2664-2677. doi: 10.1007/s11427-024-2703-6. Epub 2024 Aug 22.
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 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.
用于治疗与STING相关的炎症性疾病的STING抑制剂的开发仍面临重大挑战。STING的激活是一个多步骤过程，包括与cGAMP结合、自我寡聚化以及从内质网转运到高尔基体，最终诱导IRF3和NF-κB介导的干扰素和炎性细胞因子的表达。已经证明，破坏这些步骤中的任何一个都可以有效抑制STING的激活。传统的基于结构的药物筛选方法通常聚焦于特定的结合位点。在本研究中，采用了一种基于蛋白质一级序列且独立于结合位点的TransformerCPI模型来鉴定能够与STING蛋白结合的化合物。天然产物甘草查尔酮D（LicoD）被鉴定为一种强效且选择性的STING抑制剂。LicoD不与经典的配体结合口袋结合；相反，它共价修饰STING的Cys148残基。这种修饰抑制STING的寡聚化，从而抑制TBK1的募集以及IRF3和NF-κB的核转位。LicoD治疗改善了Trex1小鼠的炎症表型，并抑制了DSS诱导的结肠炎和AOM/DSS诱导的结肠炎相关结肠癌（CAC）的进展。总之，本研究揭示了LicoD在治疗由STING驱动的炎症性疾病方面的潜力。它还证明了TransformerCPI模型在发现传统结合口袋之外的变构化合物方面的实用性。
