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

Abstract 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.