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

Publication ,  Journal Article
Doyle, JR; Krishnaji, ST; Zhu, G; Xu, Z-Z; Heller, D; Ji, R-R; Levy, BD; Kumar, K; Kopin, AS
Published in: J Biol Chem
May 9, 2014

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.

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Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

May 9, 2014

Volume

289

Issue

19

Start / End Page

13385 / 13396

Location

United States

Related Subject Headings

  • Receptors, G-Protein-Coupled
  • Receptors, Chemokine
  • Peptides
  • Neuralgia
  • Mice
  • Male
  • Intercellular Signaling Peptides and Proteins
  • Inflammation
  • Humans
  • HEK293 Cells
 

Citation

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Doyle, J. R., Krishnaji, S. T., Zhu, G., Xu, Z.-Z., Heller, D., Ji, R.-R., … Kopin, A. S. (2014). Development of a membrane-anchored chemerin receptor agonist as a novel modulator of allergic airway inflammation and neuropathic pain. J Biol Chem, 289(19), 13385–13396. https://doi.org/10.1074/jbc.M113.522680
Doyle, Jamie R., Subrahmanian T. Krishnaji, Guangli Zhu, Zhen-Zhong Xu, Daniel Heller, Ru-Rong Ji, Bruce D. Levy, Krishna Kumar, and Alan S. Kopin. “Development of a membrane-anchored chemerin receptor agonist as a novel modulator of allergic airway inflammation and neuropathic pain.J Biol Chem 289, no. 19 (May 9, 2014): 13385–96. https://doi.org/10.1074/jbc.M113.522680.
Doyle JR, Krishnaji ST, Zhu G, Xu Z-Z, Heller D, Ji R-R, et al. 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.
Doyle, Jamie R., et al. “Development of a membrane-anchored chemerin receptor agonist as a novel modulator of allergic airway inflammation and neuropathic pain.J Biol Chem, vol. 289, no. 19, May 2014, pp. 13385–96. Pubmed, doi:10.1074/jbc.M113.522680.
Doyle JR, Krishnaji ST, Zhu G, Xu Z-Z, Heller D, Ji R-R, Levy BD, Kumar K, Kopin AS. 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):13385–13396.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

May 9, 2014

Volume

289

Issue

19

Start / End Page

13385 / 13396

Location

United States

Related Subject Headings

  • Receptors, G-Protein-Coupled
  • Receptors, Chemokine
  • Peptides
  • Neuralgia
  • Mice
  • Male
  • Intercellular Signaling Peptides and Proteins
  • Inflammation
  • Humans
  • HEK293 Cells