jm0c00377_si_001.pdf (856.52 kB)
Discovery of an Orally Active Small-Molecule Tumor Necrosis Factor‑α Inhibitor
journal contribution
posted on 2020-07-30, 22:41 authored by Weiguang Sun, Yanli Wu, Mengzhu Zheng, Yueying Yang, Yang Liu, Canrong Wu, Yirong Zhou, Yonghui Zhang, Lixia Chen, Hua LiTumor
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.