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

作　　者：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 

机构地区：[1]Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment,Zhuhai Institute of Translational Medicine,Zhuhai People’s Hospital Affiliated with Jinan University,Jinan University,Zhuhai 519000,China [2]Institute of Traditional Chinese Medicine and Natural Products,College of Pharmacy/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education(MOE)of China,Jinan University,Guangzhou 510632,China [3]Department of Respirology,Capital Medical University,Beijing 100069,China [4]Biomedical Translational Research Institute,Health Science Center(School of Medicine),Jinan University,Guangzhou 510632,China [5]State Key Laboratory of Mycology,Institute of Microbiology,Chinese Academy of Sciences,Beijing 100190,China [6]Department of Respiratory and Critical Care Medicine,the Second Affiliated Hospital of Xi’an Jiaotong University(Xibei Hospital),Xi’an 710004,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第9期3930-3944,共15页药学学报（英文版）

基　　金：supported by the National Key Research and Development Program of China(2018YFA0903200,2018YFA0903201,and 2020YFA0803502);the National Natural Science Foundation of China(81925037,U22A20371,31830021,32030036,and 82270055);the 111 Project(B16021,China);National High-level Personnel of Special Support Program(2017RA2259,China);Guangdong International Science and Technology Cooperation Base(2021A0505020015,China);Innovative and Research Teams Project of Guangdong Higher Education Institution(2021KCXTD001,China);Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y036,China);Guangdong Natural Science Funds for Distinguished Young Scholar(2021B1515020065,China)。

摘　　要：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 dosedependently 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.

关 键 词：Aureane-type sesquiterpene tetraketides IL-17A Experimental autoimmune encephalomyelitis Pulmonary hypertension 

分 类 号：R91[医药卫生—药学]