期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 15, 页码 8146-8156出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00377
关键词
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资金
- Program for Changjiang Scholars of Ministry of Education of the People's Republic of China [T2016088]
- National Science Fund for Distinguished Young Scholars [81725021]
- National Natural Science Foundation of China [81703580, 81773637, 81473254]
- Fundamental Research Fund for the Central Universities (HUST COVID-19 Rapid Response Call, China) [2020kfyXGYJ037]
Tumor necrosis factor alpha (TNF-alpha) 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-alpha and block TNF-alpha-trigged signaling activation. Furthermore, the endotoxemic murine model showed that benpyrine could attenuate TNF-alpha-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-alpha inhibitor that is potentially useful for treating TNF-alpha-mediated inflammatory and autoimmune disease.
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