The ability to engineer pharmaceuticals that target the signal-dependent interactions of signaling proteins should revolutionize drug development. One approach to the rational design of protein interaction inhibitors uses decoy peptides, i.e. segments of protein primary sequence, which are derived from interfaces that mediate functional protein interactions. Decoy peptides often retain the ability of the full-length prototype to bind the docking site of the folded protein and thereby block the signal transduction. This review summarizes advances made in the last decade in the development of cell-permeable decoy peptide (CPDP) inhibitors to target the Toll/IL-1R resistance (TIR) domain-mediated protein interactions in TLR signaling, in connection with the recent progress in understanding of the TLR signalosome assembly mechanisms. We present a large collection of currently available, TIR-targeting CPDPs and propose their classification based on the types of TIR–TIR interactions they target. The binding behavior of different CPDP-TIR pairs, studied in cell-based assays and in binary in vitro systems using recombinant TIR domains, is also reviewed. The available affinity data provide benchmarks for rapid preliminary evaluation of future inhibitors. We review literature that evaluates the in vivo potency of select CPDPs and attempt to outline the areas of forthcoming progress, towards the development of CPDP-based TLR inhibitors of pharmaceutical grade.

设计靶向信号传导蛋白信号依赖相互作用的药物的能力将彻底改变药物开发。合理设计蛋白质相互作用抑制剂的一种方法是使用诱饵肽，即蛋白质一级序列的片段，其来源于介导功能性蛋白质相互作用的界面。诱饵肽通常保留全长原型结合折叠蛋白对接位点的能力，从而阻止信号转导。这篇综述总结了最近十年在细胞渗透性诱饵肽（CPDP）抑制剂的开发中取得的进展，该抑制剂以TLR信号转导中的Toll / IL-1R抗性（TIR）域介导的蛋白质相互作用为目标，并与之相关。对TLR信号小体组装机制的了解。我们介绍了大量当前可用的，以TIR为目标的CPDP，并根据它们所针对的TIR–TIR交互作用的类型提出了它们的分类。在基于细胞的测定法和二元法中研究了不同CPDP-TIR对的结合行为还回顾了使用重组TIR结构域的体外系统。可用的亲和力数据为将来的抑制剂的快速初步评估提供了基准。我们回顾了评估某些CPDP体内效力的文献，并试图概述即将发展的领域，以开发基于CPDP的药用级TLR抑制剂。