肿瘤坏死因子 (TNF) 是一种促炎细胞因子，其功能性同源三聚体形式与 TNF 受体 (TNFR) 相互作用，激活下游细胞凋亡、坏死性凋亡和炎症信号通路。这些通路的过度激活会导致各种炎症性疾病，这使得 TNF 成为一个有前途的治疗靶点。在此，根据其相对结合能从 TNF-TNFR 界面中选择 12 聚体肽，并将其命名为“TNF 抑制诱饵”(TID)。这些诱饵肽抑制 TNF 介导的细胞因子分泌和细胞死亡，以及下游信号传导效应器的激活。有效的 TID 通过破坏 TNF 功能性同源三聚体形式的形成来抑制 TNF 信号传导。在 TID 的衍生物中，TID3c 通过破坏 TNF 三聚体的形成，在基于细胞的测定中显示出稍微更好的功效。此外，TID3c 将 TNF 寡聚成高分子量构型。计算机建模和模拟显示，TID3c 及其母肽 TID3 通过氢键和静电相互作用与 TNF 形成稳定的复合物，这使它们成为开发基于肽的抗 TNF 疗法的有希望的先导。© 2024 Federation of Europe Biochemical社团。

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.© 2024 Federation of European Biochemical Societies.