首页|Targeting STING oligomerization with licochalcone D amelio-rates STING-driven inflammatory diseases

Targeting STING oligomerization with licochalcone D amelio-rates STING-driven inflammatory diseases

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The development of STING inhibitors for the treatment of STING-related inflammatory diseases continues to encounter significant chal-lenges.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 in-flammatory 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.

cGAS-STING signalingSTING inhibitorTransformerCPI modelLicochalcone Dinflammatory diseases

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

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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

School of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing 210023,China

Shanghai Institute for Advanced Immunochemical Studies,and School of Life Science and Technology,Shanghai Tech University,Shanghai 200031,China

School of Physical Science and Technology,ShanghaiTech University,Shanghai 200031,China

School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou 310024,China

Shanghai Institute for Advanced Immunochemical S

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2024

10.1007/s11427-024-2703-6

中国科学:生命科学(英文版)
中国科学院

中国科学:生命科学(英文版)

CSTPCD
影响因子：0.806
ISSN：1674-7305
年,卷(期)：2024.67(12)