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 (Sep 2023)

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

Affiliations

Xin Tang: 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; Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China
Chuanxi Wang: 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
Lei Wang: Department of Respirology, Capital Medical University, Beijing 100069, China; Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University (Xibei Hospital), Xi'an 710004, China
Feifei Ren: Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China
Runqiao Kuang: 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
Zhenhua Li: 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; Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China
Xue Han: 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
Yiming Chen: Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China
Guodong Chen: 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
Xiuqing Wu: Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China
Jie Liu: Department of Respirology, Capital Medical University, Beijing 100069, China
Hengwen Yang: Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China
Xingzhong Liu: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100190, China
Chen Wang: Department of Respirology, Capital Medical University, Beijing 100069, China; Corresponding authors.
Hao Gao: 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; Corresponding authors.
Zhinan Yin: 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; Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China; Corresponding authors.

Journal volume & issue: Vol. 13, no. 9
pp. 3930 – 3944

Abstract

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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.

Published in Acta Pharmaceutica Sinica B

ISSN: 2211-3835 (Print); 2211-3843 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: http://www.journals.elsevier.com/acta-pharmaceutica-sinica-b

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