SLAMF1-derived peptide could limit the inflammation mediated by several Toll-like receptors

Inflammation plays a crucial role in the development and progression of most diseases and is highly dependent on pathogenic overstimulation of pattern recognition receptors (PRRs). It is, therefore, necessary to equilibrate PRRs’ signals to restore the pathogen defence and limit the detrimental consequences of excessive inflammation. One of the approaches to control PRRs’ signalling is application of small molecules or peptide-based drugs that would block protein-protein interactions (PPIs) at the critical signalling crossroads. Recently we have demonstrated that signalling lymphocyte activation molecule family 1 (SLAMF1) receptor has a critical role in regulation of signalling downstream toll-like receptor 4 (TLR4). We also defined the interaction interface for SLAMF1 and TLR4 adaptor protein TRAM. Based on these data, we developed a SLAMF1-derived peptide P7 that was linked to the cell-penetrating peptides for intracellular delivery. Inhibitory activity of P7 was tested in several experimental settings: in vitro cell cultures, primary human monocytes and macrophages, ex vivo whole-blood assays with pure TLR ligands or bacteria, and in vivo LPS-shock model. P7 strongly inhibited the pro-inflammatory signalling (TNF, IL-1beta, IL-6) and IFNbeta expression and secretion downstream several TLRs (TLR4, TLRs 7-9) and prevented the death of mice in LPS shock model. The mechanism of action of P7 peptide was linked to its interference with several PPIs: TRAM-SLAMF1, TRAM-Rab11FIP2 and TIRAP-MyD88. Overall, P7 peptide has unique mode of action, demonstrates high efficacy in vitro and in vivo and could be considered for further development as a drug for treatment of a range of TLRs-driven inflammatory diseases (TLR4, TLR7, TLR8 and TLR9).