Development Of A Membrane Anchored Chemerin Receptor Agonist As A Novel Modulator Of Inflammation

The chemerin receptor (CMKLR1) is a G protein‐coupled receptor that is found on macrophages, monocytes, and natural killer cells. CMKLR1 is primarily coupled to the inhibitory G protein, Gαi, and has been shown to modulate the resolution of inflammation. CMKLR1 is activated by both lipid and peptide agonists, resolvin E1 and chemerin. Notably, these ligands have short half‐lives. To expedite the development of long acting, stable chemerin analogs, we used membrane tethered ligand (MTL) technology. MTLs are recombinant proteins comprised of an extracellular peptide ligand, a linker sequence, and an anchoring transmembrane domain. Using this technology, we established that a 9 amino acid (aa) tethered chemerin fragment activates CMKLR1 with efficacy exceeding that of the full length peptide (137 aa). To enable in vivo delivery of a corresponding anchored peptide (an MTL mimick) we generated a lipidated analog of the 9 aa fragment. Pharmacological assessment revealed high potency and wash resistance (an index of membrane anchoring). Subsequent amino acid modification resulted in a short, proteolysis‐resistant, lipidated peptide that activated mouse and human CMKLR1. Preliminary data suggests that this ligand, when applied to airway mucosal surfaces, abrogates inflammation in an animal model of asthma. Work is in progress to assess this molecule as a candidate modulator of other inflammatory diseases.