Targeting the TLR signalosome with TIR domain-derived cell-permeable decoy peptides: the current state and perspectives

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.