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Designed CXCR4 mimic acts as a soluble chemokine receptor that blocks atherogenic inflammation by agonist-specific targeting
- Source :
- Nature Communications, Vol 11, Iss 1, Pp 1-18 (2020), Nature Communications, 11(1):5981. Nature Publishing Group, Nature Communications
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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−/− 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.<br />The development of specific anti-cytokine/chemokine therapeutic strategies for atherosclerotic disease is challenging. Here, the authors have designed a peptide-based ectodomain mimic of the chemokine receptor CXCR4 that selectively targets MIF but not CXCL12 and blocks experimental atherosclerosis in vivo.
- Subjects :
- Male
EXPRESSION
Receptors, CXCR4
Carotid Artery, Common
Mice, Knockout, ApoE
Science
Drug Evaluation, Preclinical
610 Medicine & health
1600 General Chemistry
CELL-DERIVED FACTOR-1-ALPHA
Crystallography, X-Ray
MIGRATION-INHIBITORY FACTOR
MOUSE
Article
Mice
Antigens, CD
1300 General Biochemistry, Genetics and Molecular Biology
BINDING
otorhinolaryngologic diseases
Animals
Humans
Macrophage Migration-Inhibitory Factors
Aged
Inflammation
Endarterectomy, Carotid
Binding Sites
Middle Aged
CXCL12
Chemokine CXCL12
Peptide Fragments
Sialyltransferases
3100 General Physics and Astronomy
FACTOR MIF
biological factors
Intramolecular Oxidoreductases
Disease Models, Animal
CYTOKINE
ATHEROSCLEROSIS
Drug Design
11548 Clinic for Vascular Surgery
Cytokines
Female
Structure-based drug design
LIGAND
Peptides
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 11
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.pmid.dedup....1181f49528ed27d8f1bf084ea967e9f1
- Full Text :
- https://doi.org/10.1038/s41467-020-19764-z