Peptide-Based Regulation of TNF-α-Mediated Cytotoxicity

Tumor necrosis factor alpha (TNF-alpha) is a pro-inflammatory cytokine associated with TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2), which play important roles in several inflammatory diseases. There is a growing interest in developing alternative molecules that can be used as TNF blockers. In this study, we focused on TNF-alpha-, TNFR1-, and TNFR2-mimicking peptides to inhibit TNF-alpha receptor binding in various ways. Six peptides (OB1, OB2, OB5, OB6, OB7, and OB8) were developed to bind TNFR1, TNFR2, and TNF-alpha. OB1 and OB2 bound to TNF-alpha with lower Kd values of 300 and 46.7 nM, respectively, compared to previously published sequences. These synthetic peptides directly and indirectly inhibited TNF-alpha in vitro without cytotoxicity to L929 cells, and OB1 significantly inhibited apoptosis in the presence of hTNF-alpha. Peptides developed in this study may prove to be useful for therapeutic inhibition of TNF-alpha.