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Designed CXCR4 mimic acts as a soluble chemokine receptor that blocks atherogenic inflammation by agonist-specific targeting.
- Source :
-
Nature communications [Nat Commun] 2020 Nov 25; Vol. 11 (1), pp. 5981. Date of Electronic Publication: 2020 Nov 25. - Publication Year :
- 2020
-
Abstract
- 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 <superscript>-/-</superscript> 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.
- Subjects :
- Aged
Animals
Antigens, CD metabolism
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 metabolism
Macrophage Migration-Inhibitory Factors metabolism
Male
Mice
Mice, Knockout, ApoE
Middle Aged
Peptide Fragments therapeutic use
Receptors, CXCR4 chemistry
Receptors, CXCR4 ultrastructure
Sialyltransferases metabolism
Signal Transduction drug effects
Atherosclerosis drug therapy
Intramolecular Oxidoreductases antagonists & inhibitors
Macrophage Migration-Inhibitory Factors antagonists & inhibitors
Peptide Fragments pharmacology
Receptors, CXCR4 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 33239628
- Full Text :
- https://doi.org/10.1038/s41467-020-19764-z