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Title: Development of highly potent protease-activated receptor 2 agonists via synthetic lipid tethering.

Authors: Flynn, Andrea N; Hoffman, Justin; Tillu, Dipti V; Sherwood, Cara L; Zhang, Zhenyu; Patek, Renata; Asiedu, Marina N K; Vagner, Josef; Price, Theodore J; Boitano, Scott

Published In FASEB J, (2013 Apr)

Abstract: Protease-activated receptor-2 (PAR₂) is a G-protein coupled receptor (GPCR) associated with a variety of pathologies. However, the therapeutic potential of PAR₂ is limited by a lack of potent and specific ligands. Following proteolytic cleavage, PAR₂ is activated through a tethered ligand. Hence, we reasoned that lipidation of peptidomimetic ligands could promote membrane targeting and thus significantly improve potency and constructed a series of synthetic tethered ligands (STLs). STLs contained a peptidomimetic PAR₂ agonist (2-aminothiazol-4-yl-LIGRL-NH₂) bound to a palmitoyl group (Pam) via polyethylene glycol (PEG) linkers. In a high-throughput physiological assay, these STL agonists displayed EC₅₀ values as low as 1.47 nM, representing a ∼200 fold improvement over the untethered parent ligand. Similarly, these STL agonists were potent activators of signaling pathways associated with PAR₂: EC₅₀ for Ca(2+) response as low as 3.95 nM; EC₅₀ for MAPK response as low as 9.49 nM. Moreover, STLs demonstrated significant improvement in potency in vivo, evoking mechanical allodynia with an EC₅₀ of 14.4 pmol. STLs failed to elicit responses in PAR2(-/-) cells at agonist concentrations of >300-fold their EC₅₀ values. Our results demonstrate that the STL approach is a powerful tool for increasing ligand potency at PAR₂ and represent opportunities for drug development at other protease activated receptors and across GPCRs.

PubMed ID: 23292071 Exiting the NIEHS site

MeSH Terms: Calcium Signaling/drug effects*; Calcium/metabolism; Cell Line/drug effects; Humans; Hyperalgesia/drug therapy; Ligands; Lipid Metabolism/drug effects*; Ornithine/analogs & derivatives; Ornithine/pharmacology; Palmitates/pharmacology*; Peptidomimetics/pharmacology*; Receptor, PAR-2/agonists*; Structure-Activity Relationship

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