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.
摘要：
肿瘤坏死因子（TNF）是一种促炎细胞因子，其功能性同三聚体形式与TNF受体（TNFR）相互作用以激活下游凋亡，坏死,和炎症信号通路。这些途径的过度激活导致各种炎性疾病,这使得TNF成为一个有希望的治疗靶点。这里,基于它们的相对结合能从TNF-TNFR的界面中选择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，以及下游信号效应的激活。有效的TIDs通过破坏TNF的功能性同三聚体形式的形成来抑制TNF信号传导。在TID的衍生物中，通过破坏TNF三聚体形成,TID3c在基于细胞的测定中显示稍微更好的功效。此外，TID3c将TNF寡聚化为高分子量构型。计算机建模和模拟表明，TID3c及其亲本肽，TID3，通过氢键和静电相互作用与TNF形成稳定的复合物，这使他们成为开发基于肽的抗TNF治疗剂的有希望的领导者。
