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

Abstract

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.

Overcoming cancer risk in inflammatory bowel disease: new insights into preventive strategies and pathogenesis mechanisms including interactions of immune cells, cancer signaling pathways, and gut microbiota

“…The specific factors that directly induce NF-κB activation during the progression of CAC remain unclear. One potential mediator in the epithelial cells of patients with IBD is TNF-α, which is significantly elevated in the inflamed intestinal environment ( 155 ). And TNFR2 signaling in intestinal epithelial cells may directly contribute to the development of persistent CAC.…”