期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 19, 页码 13385-13396出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.522680
关键词
Allergy; Drug Screening; G Protein-coupled Receptors (GPCR); Inflammation; Pharmacology; CMKLR1; ChemR23; Lipidated Peptides; Membrane-tethered Ligands
资金
- National Institutes of Health [R01-DK072497, T32-HL069770, R01-HL068669, P01-GM095467, R01-GM65500, R01-CA125033, R01-NS67686]
Background: The chemerin-CMKLR1 axis modulates inflammation; ligands for CMKLR1 have short half-lives. Results: We have utilized a novel technology to develop a long-acting, high potency membrane-anchored CMKLR1 agonist. Conclusion: This ligand decreases allergic airway inflammation and neuropathic pain in mice. Significance: Our approach can be applied to develop other candidate therapeutics targeting peptide hormone receptors implicated as modulators of disease. 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, G(i), 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据