State Key Laboratory of Chemical Oncogenomics, Guangdong Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
Shenzhen Bay Laboratory, Shenzhen, 518055, China.
Chem Biodivers. 2024 Oct;21(10):e202401253. doi: 10.1002/cbdv.202401253. Epub 2024 Sep 4.
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.
环鸟苷酸-腺苷酸合酶 (cGAS)-干扰素基因刺激蛋白 (STING) 信号通路是先天免疫的关键组成部分，在抵御病原体感染和细胞应激方面发挥着重要作用。然而，cGAS-STING 通路的异常激活与炎症性和自身免疫性疾病有关。在这里，我们通过环化 STING 的 N 端尾巴 (NTT) 开发了环肽 STING 抑制剂。这些环肽选择性地抑制了人或鼠细胞系中 STING 通路的激活。在机制上，抑制剂直接与 STING 结合，随后阻止了 STING 的聚集和激活。此外，最佳抑制剂 STi-2 显著抑制了 Trex1 小鼠的促炎细胞因子产生和全身炎症。总的来说，我们的工作促进了 STING 的特异性抑制剂的开发，作为治疗 cGAS-STING 相关自身炎症性疾病的潜在疗法。
