PAR-2 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 mimics the sequence of the ‘tethered ligand’ and is therefore capable of activating the receptor independently of N-terminal proteolysis. SLIGRL-NH2 inhibits the development of airway eosinophilia, hyper-responsiveness and displays bronchodilator activity in allergic mice and also facilitates gastrointestinal transit in mice-in vivo. PAR activation has been linked to inflammation, therefore compounds that mimic or interfere with the PAR-activating processes are attractive therapeutic candidates.