Discovery of an Orally Active Small-Molecule Tumor Necrosis Factor-α Inhibitor

作     者：Sun, Weiguang Wu, Yanli Zheng, Mengzhu Yang, Yueying Liu, Yang Wu, Canrong Zhou, Yirong Zhang, Yonghui Chen, Lixia Li, Hua 

作者机构：Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation School of Pharmacy Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China Wuya College of Innovation Key Laboratory of Structure-Based Drug Design and Discovery Ministry of Education Shenyang Pharmaceutical University Shenyang 110016 China 

出 版 物：《Journal of Medicinal Chemistry》 (J. Med. Chem.)

年 卷 期：2020年第63卷第15期

页      面：8146-8156页

学科分类：0710[理学-生物学] 1007[医学-药学(可授医学、理学学位)] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 0703[理学-化学] 10[医学] 

基　　金：National Natural Science Foundation of China, NSFC, (81473254, 81703580, 81773637) National Natural Science Foundation of China, NSFC Ministry of Education of the People's Republic of China, MOE, (T2016088) Ministry of Education of the People's Republic of China, MOE Huazhong University of Science and Technology, HUST, (2020kfyXGYJ037) Huazhong University of Science and Technology, HUST Fundamental Research Funds for the Central Universities National Science Fund for Distinguished Young Scholars, (81725021) National Science Fund for Distinguished Young Scholars 

主　　题：Anatomy Serum Rodent models Peptides and proteins Inflammation 

摘      要：Tumor necrosis factor α (TNF-α) is an important therapeutic target for rheumatoid arthritis, inflammatory bowel disease, and septic hepatitis. In this study, structure-based virtual ligand screening combined with in vitro and in vivo assays were applied. A lead compound, benpyrine, could directly bind to TNF-α and block TNF-α-trigged signaling activation. Furthermore, the endotoxemic murine model showed that benpyrine could attenuate TNF-α-induced inflammation, thereby reducing liver and lung injury. Meanwhile, administration of benpyrine by gavage significantly relieved the symptoms of collagen-induced arthritis and imiquimod-induced psoriasiform inflammation in mice. Thus, our study discovered a novel, highly specific, and orally active small-molecule TNF-α inhibitor that is potentially useful for treating TNF-α-mediated inflammatory and autoimmune disease. © 2020 American Chemical Society.