ArticlePloS one2014
Development and evaluation of small peptidomimetic ligands to protease-activated receptor-2 (PAR2) through the use of lipid tethering.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers, 1 of them a synthesis that pooled it.
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Who cites it
14 citing papers in PubMed, 1 synthesis or guideline pooled it, 18 citations in OpenAlex.
- Characterization and Functions of Protease-Activated Receptor 2 in Obesity, Diabetes, and Metabolic Syndrome: A Systematic Review.BioMed research international · 2016Pooled it
- PAR2 activation in the dura causes acute behavioral responses and priming to glyceryl trinitrate in a mouse migraine model.The journal of headache and pain · 2023Article
- C781, a β-Arrestin Biased Antagonist at Protease-Activated Receptor-2 (PAR2), Displays in vivo Efficacy Against Protease-Induced Pain in Mice.The journal of pain · 2023Article
- β-Arrestin-biased proteinase-activated receptor-2 antagonist C781 limits allergen-induced airway hyperresponsiveness and inflammation.British journal of pharmacology · 2023Article
- Protease-activated receptors in health and disease.Physiological reviews · 2023Review
- PAR2 Deficiency Induces Mitochondrial ROS Generation and Dysfunctions, Leading to the Inhibition of Adipocyte Differentiation.Oxidative medicine and cellular longevity · 2021Article
- Discovery of Novel Nonpeptidic PAR2 Ligands.ACS medicinal chemistry letters · 2020Article
- The cellular basis of protease-activated receptor 2-evoked mechanical and affective pain.JCI insight · 2020Article
- Protease activated receptor 2 (PAR2) activation causes migraine-like pain behaviors in mice.Cephalalgia : an international journal of headache · 2019Article
- Lipidated connexin mimetic peptides potently inhibit gap junction-mediated CaAmerican journal of physiology. Cell physiology · 2018Article
- Bronchoprotection and bronchorelaxation in asthma: New targets, and new ways to target the old ones.Pharmacology & therapeutics · 2016Review
- Imaging of targeted lipid microbubbles to detect cancer cells using third harmonic generation microscopy.Biomedical optics express · 2016Article
- The novel PAR2 ligand C391 blocks multiple PAR2 signalling pathways in vitro and in vivo.British journal of pharmacology · 2015Article
- A highly potent agonist to protease-activated receptor-2 reveals apical activation of the airway epithelium resulting in Ca2+-regulated ion conductance.American journal of physiology. Cell physiology · 2014Article
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
Protease-activated receptor-2 (PAR2) is a G-Protein Coupled Receptor (GPCR) activated by proteolytic cleavage to expose an attached, tethered ligand (SLIGRL). We evaluated the ability for lipid-tethered-peptidomimetics to activate PAR2 with in vitro physiological and Ca2+ signaling assays to determine minimal components necessary for potent, specific and full PAR2 activation. A known PAR2 activating compound containing a hexadecyl (Hdc) lipid via three polyethylene glycol (PEG) linkers (2at-LIGRL-PEG3-Hdc) provided a potent agonist starting point (physiological EC50 = 1.4 nM; 95% CI: 1.2-2.3 nM). In a set of truncated analogs, 2at-LIGR-PEG3-Hdc retained potency (EC50 = 2.1 nM; 1.3-3.4 nM) with improved selectivity for PAR2 over Mas1 related G-protein coupled receptor type C11, a GPCR that can be activated by the PAR2 peptide agonist, SLIGRL-NH2. 2at-LIG-PEG3-Hdc was the smallest full PAR2 agonist, albeit with a reduced EC50 (46 nM; 20-100 nM). 2at-LI-PEG3-Hdc retained specific activity for PAR2 with reduced EC50 (310 nM; 260-360 nM) but displayed partial PAR2 activation in both physiological and Ca2+ signaling assays. Further truncation (2at-L-PEG3-Hdc and 2at-PEG3-Hdc) eliminated in vitro activity. When used in vivo, full and partial PAR2 in vitro agonists evoked mechanical hypersensitivity at a 15 pmole dose while 2at-L-PEG3-Hdc lacked efficacy. Minimum peptidomimetic PAR2 agonists were developed with known heterocycle substitutes for Ser1 (isoxazole or aminothiazoyl) and cyclohexylalanine (Cha) as a substitute for Leu2. Both heterocycle-tetrapeptide and heterocycle-dipeptides displayed PAR2 specificity, however, only the heterocycle-tetrapeptides displayed full PAR2 agonism. Using the lipid-tethered-peptidomimetic approach we have developed novel structure activity relationships for PAR2 that allows for selective probing of PAR2 function across a broad range of physiological systems.
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