PAR-2 receptor agonist – GPCR Modulators

Protease activated receptors (PARs) are a distinctive four-member family of seven transmembrane G protein-coupled receptors (GPCRs) widely expressed in inflammatory cells. PARs are cleaved by certain serine proteases to expose a tethered ligand domain, this ligand domain then binds to and activates the receptors to initiate multiple signalling cascades. These PAR-activating proteases therefore represent PAR agonists. This PAR-2 agonist peptide represents the sequence of the ‘tethered ligand’ and is therefore capable of activating the receptor independently of N-terminal proteolysis. This peptide has been shown to elicit a range of cellular responses including- histamine release from skin mast cells- IL-8 and lactoferrin secretion from peripheral blood neutrophils- increased vascular cell adhesion molecule-1 (VCAM-1) expression- release of IL-8 and granulocyte colony-stimulating factor (G-CSF) from bronchial fibroblasts- secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF), intercellular adhesion molecule 1 (ICAM-1), tumour necrosis factor alpha (TNF-α), matrix metalloproteinase-1 (MMP-1), and MMP-10 from epithelial cells- and production of thymic stromal lymphopoietin (TSLP) in the skin of mice and its release from T cells. PAR activation has been linked to inflammation and an increase in PAR-2 expression is seen in patients with septic shock.- Therefore compounds that-mimic or interfere with the PAR-activating processes are attractive therapeutic candidates.