Fusheng Guo, Jing Zhang, Yihui Gao, Zhou
Shu, Fei Sun, Jing Ma, Xu Zhou, Wenyang Li, Huawei
Mao*, Xiaoguang Lei*
Angew. Chem. Int. Ed. 2024, e202407641
Excessive activation of the stimulator of the interferon gene (STING) pathway has been identified as a significant contributor to various autoimmune diseases, such as STINGassociated vasculopathy with infantile-onset (SAVI) and inflammatory bowel disease (IBD). However, discovering effective STING antagonists for treating STING-mediated autoimmune disorders remains challenging. Herein, we identified the natural product anhydrotuberosin (ATS) as a potent STING antagonist by a high-throughput chemical screen and follow-up biological validations. However, the limited supply from natural product isolation impeded the pharmacological evaluations of ATS. Accordingly, we developed a concise and scalable total synthesis of ATS in 6 steps. Enabled by total synthesis, we further extensively investigated ATS’s mode of action and evaluated its therapeutic potential. Remarkably, ATS inhibits STING signaling in PBMCs derived from three SAVI patients. ATS showed decent pharmacokinetic parameters and strongly alleviated tissue inflammation in DSS-induced IBD colitis and Trex1-/- autoimmune animal models with low toxicity. Collectively, this research lays the foundation for developing novel STING antagonists as an effective therapy for autoinflammatory and autoimmune diseases.