1.Aureane-type sesquiterpene tetraketides as a novel class of immunomodulators with interleukin-17A inhibitory activity.
Xin TANG ; Chuanxi WANG ; Lei WANG ; Feifei REN ; Runqiao KUANG ; Zhenhua LI ; Xue HAN ; Yiming CHEN ; Guodong CHEN ; Xiuqing WU ; Jie LIU ; Hengwen YANG ; Xingzhong LIU ; Chen WANG ; Hao GAO ; Zhinan YIN
Acta Pharmaceutica Sinica B 2023;13(9):3930-3944
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.
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