Decoy peptides that inhibit TNF signaling by disrupting the TNF homotrimeric oligomer

Abstract

Tumor necrosis factor (TNF) is a pro‐inflammatory cytokine and its functional homotrimeric form interacts with the TNF receptor (TNFR) to activate downstream apoptotic, necroptotic, and inflammatory signaling pathways. Excessive activation of these pathways leads to various inflammatory diseases, which makes TNF a promising therapeutic target. Here, 12‐mer peptides were selected from the interface of TNF‐TNFR based upon their relative binding energies and were named ‘TNF‐inhibiting decoys’ (TIDs). These decoy peptides inhibited TNF‐mediated secretion of cytokines and cell death, as well as activation of downstream signaling effectors. Effective TIDs inhibited TNF signaling by disrupting the formation of TNF's functional homotrimeric form. Among derivatives of TIDs, TID3c showed slightly better efficacy in cell‐based assays by disrupting TNF trimer formation. Moreover, TID3c oligomerized TNF to a high molecular weight configuration. In silico modeling and simulations revealed that TID3c and its parent peptide, TID3, form a stable complex with TNF through hydrogen bonds and electrostatic interactions, which makes them the promising lead to develop peptide‐based anti‐TNF therapeutics.