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Development of Antagonists for the Protease Activated Receptor‐2
Author(s) -
Hoffman Justin,
Flynn Andrea,
Tillu Dipti V,
Sherwood Cara L,
Zhang Zhenyu,
Patek Renata,
Vagner Josef,
Price Theodore J,
Boitano Scott
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.803.12
Subject(s) - peptidomimetic , protease , chemistry , trypsin , g protein coupled receptor , stereochemistry , biochemistry , receptor , peptide , enzyme
P rotease a ctivated r eceptor‐2 (PAR 2 ) is a G‐Protein Coupled Receptor with a significant role in many diseases including allergic asthma and chronic pain. PAR 2 is activated by protease cleavage to reveal tethered ligand sequences that bind the receptor to initiate intracellular signaling. Peptide/peptidomimetic ligands based on the primary trypsin cleavage site have been explored as PAR 2 agonists/antagonists. We describe a PAR 2 peptidomimetic (C391) derived from the major trypsin cleavage site sequence (SLIGRL) that blocks both PAR 2 peptidomimetic and protease induced signaling in vitro and thermal hyperalgesia in vivo . We also describe the first antagonists developed from the primary Kallikrein14 cleavage site sequence (SSKGRS). Kallikrein14 derived peptidomimetic antagonist potency was increased through palmitoylation (Pam) with polyethylene glycol spacers (PEGs) to construct synthetic tethered ligands. We demonstrate that: 1) these ligands bind to PAR 2 ; 2) do not directly stimulate cell signaling pathways (e.g., Ca 2+ , MAPK); 3) do not limit trypsin‐like protease activity; and 4) inhibit trypsin‐like protease and peptidomimetic‐induced PAR 2 signaling. These peptidomimetics represent a novel set of high potency PAR 2 antagonists.