Cyclopeptide Inhibitors Target the N-Terminal Tail of STING and Alleviate Autoinflammation

被引：2

作者：

Wang, Xiaoquan ^{[1
]}

Cao, Anqi ^{[1
]}

Zheng, Wenlv ^{[1
]}

Quan, Junmin ^{[1
,2
]}

机构：

[1] Peking Univ, Shenzhen Grad Sch, State Key Lab Chem Oncogen, Guangdong Key Lab Chem Genom, Shenzhen 518055, Peoples R China

[2] Shenzhen Bay Lab, Shenzhen 518055, Peoples R China

来源：

CHEMISTRY & BIODIVERSITY | 2024年 / 21卷 / 10期

关键词：

STING; Autoinflammation; Inhibitor; Cyclopeptide; CYCLIC GMP-AMP; INNATE IMMUNE SENSOR; DNA SENSOR; PATHWAY; SYNTHASE; 2ND-MESSENGER; DINUCLEOTIDE; ADAPTER; LIGAND; IRF3;

D O I：

10.1002/cbdv.202401253

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is a crucial component of innate immunity that plays a vital role in protecting against pathogen infections and cellular stress. However, aberrant activation of cGAS-STING pathway is related to inflammatory and autoimmune diseases. Here, we developed cyclopeptide STING inhibitors by cyclizing the N-terminal tail (NTT) of STING. These cyclopeptides selectively inhibited the activation of STING pathway in human or murine cell lines. Mechanistically, the inhibitors directly bound to STING, and subsequently blocked the aggregation and activation of STING. In addition, the optimal inhibitor STi-2 significantly suppressed proinflammatory cytokine production and systemic inflammation in Trex1-/- mice. Overall, our work facilitates the development of specific inhibitors of STING as potential therapies for cGAS-STING associated autoinflammatory diseases. image

引用

页数：8

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