Designed CXCR4 mimic acts as a soluble chemokine receptor that blocks atherogenic inflammation by agonist-specific targeting

Nat Commun. 2020 Nov 25;11(1):5981. doi: 10.1038/s41467-020-19764-z.


Targeting a specific chemokine/receptor axis in atherosclerosis remains challenging. Soluble receptor-based strategies are not established for chemokine receptors due to their discontinuous architecture. Macrophage migration-inhibitory factor (MIF) is an atypical chemokine that promotes atherosclerosis through CXC-motif chemokine receptor-4 (CXCR4). However, CXCR4/CXCL12 interactions also mediate atheroprotection. Here, we show that constrained 31-residue-peptides ('msR4Ms') designed to mimic the CXCR4-binding site to MIF, selectively bind MIF with nanomolar affinity and block MIF/CXCR4 without affecting CXCL12/CXCR4. We identify msR4M-L1, which blocks MIF- but not CXCL12-elicited CXCR4 vascular cell activities. Its potency compares well with established MIF inhibitors, whereas msR4M-L1 does not interfere with cardioprotective MIF/CD74 signaling. In vivo-administered msR4M-L1 enriches in atherosclerotic plaques, blocks arterial leukocyte adhesion, and inhibits atherosclerosis and inflammation in hyperlipidemic Apoe-/- mice in vivo. Finally, msR4M-L1 binds to MIF in plaques from human carotid-endarterectomy specimens. Together, we establish an engineered GPCR-ectodomain-based mimicry principle that differentiates between disease-exacerbating and -protective pathways and chemokine-selectively interferes with atherosclerosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Aged
  • Animals
  • Antigens, CD / metabolism
  • Atherosclerosis / drug therapy*
  • Atherosclerosis / genetics
  • Atherosclerosis / pathology
  • Atherosclerosis / surgery
  • Binding Sites
  • Carotid Artery, Common / pathology
  • Carotid Artery, Common / surgery
  • Chemokine CXCL12 / metabolism
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Drug Design
  • Drug Evaluation, Preclinical
  • Endarterectomy, Carotid
  • Female
  • Humans
  • Intramolecular Oxidoreductases / antagonists & inhibitors*
  • Intramolecular Oxidoreductases / metabolism
  • Macrophage Migration-Inhibitory Factors / antagonists & inhibitors*
  • Macrophage Migration-Inhibitory Factors / metabolism
  • Male
  • Mice
  • Mice, Knockout, ApoE
  • Middle Aged
  • Peptide Fragments / pharmacology*
  • Peptide Fragments / therapeutic use
  • Receptors, CXCR4 / chemistry
  • Receptors, CXCR4 / metabolism*
  • Receptors, CXCR4 / ultrastructure
  • Sialyltransferases / metabolism
  • Signal Transduction / drug effects


  • Antigens, CD
  • CXCL12 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Macrophage Migration-Inhibitory Factors
  • Peptide Fragments
  • Receptors, CXCR4
  • Sialyltransferases
  • ST6GAL1 protein, human
  • Intramolecular Oxidoreductases
  • MIF protein, human
  • Mif protein, mouse