Discovery of an Anti-TNF‑α 9‑mer Peptide from a T7 Phage Display Library for the Treatment of Inflammatory Bowel Disease

• Published in: Journal of medicinal chemistry 2023-05, Vol.66 (10), p.6981-6993
• Main Authors: Wang, Helin, Wang, Junjie, Zhao, Xin, Ye, Ruiwei, Sun, Li, Wang, Jiaojiao, Li, Linxue, Liang, Hong, Wang, Sheng, Lu, Yiming
• Format: Article
• Language: English
• Subjects: Animals; Bacteriophage T7 - metabolism; Dextran Sulfate; Inflammation; Inflammatory Bowel Diseases - drug therapy; Mice; Molecular Docking Simulation; NF-kappa B - metabolism; Peptides - pharmacology; Peptides - therapeutic use; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c00436

Inhibiting TNF-α-mediated acute inflammation is an effective treatment against inflammatory bowel disease. In this study, TNF-α-based T7 phage display library screening combined with in vitro and in vivo assays was applied. A lead peptide, pep2 (ACHAWAPTR, K D = 5.14 μM), could directly bind to TNF-α and block TNF-α-triggered signaling activation. Peptide pep2 inhibits TNF-α-induced cytotoxicity and attenuates the inflammation by decreasing NF-κB and MAPK signaling activities in a variety of cells. Furthermore, pep2 attenuated colitis induced by dextran sodium sulfate in mice in both prophylactic and therapeutic settings. Moreover, pep2 reduced the phosphorylation of p38, ERK1/2, JNK1/2, p65, and IκBα in colonic tissues as well as downregulated inflammatory genes. And HIS3, TRP5, and ARG9 may be the key amino acids in pep2 to bind TNF-α by molecular docking. Collectively, targeting TNF-α with pep2 can attenuate the inflammation in vivo and vitro by inhibiting NF-κB and MAPK signaling pathways.