Development of a membrane-anchored chemerin receptor agonist as a novel modulator of allergic airway inflammation and neuropathic pain

J Biol Chem. 2014 May 9;289(19):13385-96. doi: 10.1074/jbc.M113.522680. Epub 2014 Mar 21.


The chemerin receptor (CMKLR1) is a G protein-coupled receptor found on select immune, epithelial, and dorsal root ganglion/spinal cord neuronal cells. CMKLR1 is primarily coupled to the inhibitory G protein, Gαi, and has been shown to modulate the resolution of inflammation and neuropathic pain. CMKLR1 is activated by both lipid and peptide agonists, resolvin E1 and chemerin, respectively. Notably, these ligands have short half-lives. To expedite the development of long acting, stable chemerin analogs as candidate therapeutics, we used membrane-tethered ligand technology. Membrane-tethered ligands 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-tethered chemerin fragment (amino acids 149-157) activates both mouse and human CMKLR1 with efficacy exceeding that of the full-length peptide (amino acids 21-157). To enable in vivo delivery of a corresponding soluble membrane anchored ligand, we generated lipidated analogs of the 9-amino acid fragment. Pharmacological assessment revealed high potency and wash resistance (an index of membrane anchoring). When tested in vivo, a chemerin SMAL decreased allergic airway inflammation and attenuated neuropathic pain in mice. This compound provides a prototype membrane-anchored peptide for the treatment of inflammatory disease. A parallel approach may be applied to developing therapeutics targeting other peptide hormone G protein-coupled receptors.

Keywords: Allergy; CMKLR1; ChemR23; Drug Screening; G Protein-coupled Receptors (GPCR); Inflammation; Lipidated Peptides; Membrane-tethered Ligands; Pharmacology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Asthma / drug therapy*
  • Asthma / genetics
  • Asthma / metabolism
  • Chemokines / chemistry
  • Chemokines / genetics
  • Chemokines / pharmacology*
  • Chemotactic Factors / chemistry
  • Chemotactic Factors / genetics
  • Chemotactic Factors / pharmacology*
  • HEK293 Cells
  • Humans
  • Inflammation / drug therapy
  • Inflammation / genetics
  • Inflammation / metabolism
  • Intercellular Signaling Peptides and Proteins / chemistry
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / pharmacology*
  • Male
  • Mice
  • Neuralgia / drug therapy*
  • Neuralgia / genetics
  • Neuralgia / metabolism
  • Peptides / chemistry
  • Peptides / genetics
  • Peptides / pharmacology*
  • Receptors, Chemokine / agonists*
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / metabolism
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism


  • CMKLR1 protein, human
  • CMKLR1 protein, mouse
  • Chemokines
  • Chemotactic Factors
  • Intercellular Signaling Peptides and Proteins
  • Peptides
  • RARRES2 protein, human
  • Receptors, Chemokine
  • Receptors, G-Protein-Coupled
  • chemerin protein, mouse