Aureane-type sesquiterpene tetraketides as a novel class of immunomodulators with interleukin-17A inhibitory activity

作者：Xin Tang, Chuanxi Wang, Chuanxi Wang, Lei Wang, Feifei Ren, Runqiao Kuang, Zhenhua Li, Xue Han, Yiming Chen, Guo‐Dong Chen, Xiuqing Wu, Jie Liu, Hengwen Yang, Xingzhong Liu, Chen Wang, Chen Wang, Hao Gao, Zhinan Yin · 发表于：Acta Pharmaceutica Sinica B · 年份：2023 · DOI：10.1016/j.apsb.2023.03.017 · 被引用次数：10 · 研究领域：Fungal Biology and Applications、Phytochemistry and Bioactive Compounds、Microbial Natural Products and Biosynthesis

Interleukin (IL)-17A, a pro-inflammatory cytokine, is a fundamental function in the onset and advancement of multiple immune diseases. To uncover the primary compounds with IL-17A inhibitory activity, a large-scale screening of the library of traditional Chinese medicine constituents and microbial secondary metabolites was conducted using splenic cells from IL-17A-GFP reporter mice cultured under Th17-priming conditions. Our results indicated that some aureane-type sesquiterpene tetraketides isolated from a wetland mud-derived fungus, Myrothecium gramineum, showed remarkable IL-17A inhibitory activity. Nine new aureane-type sesquiterpene tetraketides, myrogramins A–I (1, 4–11), and two known ones (2 and 3) were isolated and identified from the strain. Compounds 1, 3, 4, 10, and 11 exhibited significant IL-17A inhibitory activity. Among them, compound 3, with a high fermentation yield dose-dependently inhibited the generation of IL-17A and suppressed glycolysis in splenic cells under Th17-priming conditions. Strikingly, compound 3 suppressed immunopathology in both IL-17A-mediated animal models of experimental autoimmune encephalomyelitis and pulmonary hypertension. Our results revealed that aureane-type sesquiterpene tetraketides are a novel class of immunomodulators with IL-17A inhibitory activity, and hold great promise applications in treating IL-17A-mediated immune diseases.