SCHOOL of nature: ligand-independent immunomodulatory peptides

Groundbreaking studies in protein biophysics have identified the mechanisms of transmembrane signaling at the level of druggable protein–protein interactions (PPIs). This resulted in the development of the signaling chain homooligomerization (SCHOOL) strategy to modulate cell responses using receptor-specific peptides. Inspired by nature, these short peptides use ligand-independent mechanisms of receptor inhibition and demonstrate potent efficacy in vitro and in vivo. The SCHOOL strategy is especially important when receptor ligands are unknown. An example is the triggering receptor expressed on myeloid cells-1 (TREM-1) receptor, an emerging therapeutic target involved in the pathogenesis of most inflammatory diseases. Here, I discuss advances in the field with a focus on TREM-1 inhibitory SCHOOL peptides that offer new hope for a ‘magic bullet’ cure for cancer, arthritis, sepsis, retinopathy, and other medical challenges.