Protease-Activated Receptors (PARs) as Therapeutic Targets: Development of Agonists / Antagonists and Modulation of Gastrointestinal Functions

Abstract

Protease-activated receptors (PARs), a family of G-protein-coupled seven-transmembrane-domain receptors, are activated by proteolytic unmasking of the N-terminal cryptic tethered ligand by certain serine proteases. Among four PAR family members cloned to date, PAR-1, PAR-2 and PAR-4 can also be activated through a non-enzymatic mechanism, which is achieved by direct binding of exogenously applied synthetic peptides based on the tethered ligand sequence, namely PARs-activating peptides, to the body of the receptor. Various peptide mimetics have been synthesized as agonists and / or antagonists for PARs with improved potency, selectivity and stability. The amidation of the C-terminal of PARs-activating peptides increases the potency and metabolic resistance, particularly in vivo . Substitution of the Nterminal serine residue of PAR-2-activating peptides with a furoyl group dramatically enhances both potency and metabolic resistance, providing the most potent PAR-2 agonist. Some peptide mimetics and / or non-peptide compounds have also been developed as antagonists for PAR-1 and PAR-4. PARs are widely distributed in the mammalian body, especially throughout the alimentary systems, and play various roles in physiological / pathophysiological conditions; i.e. modulation of salivary, gastric or pancreatic glandular exocrine secretion and gastrointestinal smooth muscle motility, gastric mucosal cytoprotection, suppression / facilitation of visceral pain and inflammation, etc. Thus, PARs are now considered novel therapeutic targets, and development of selective agonists and / or antagonists for PARs might provide novel strategy for clinical treatment of various diseases that are resistant to current therapeutics. Keywords: protease (proteinase)-activated receptor (par), protease, structure-activity relationship, gastrointestinal tract