Designed CXCR4 mimic acts as a soluble chemokine receptor that blocks atherogenic inflammation by agonist-specific targeting.
Aged
Animals
Antigens, CD
/ metabolism
Atherosclerosis
/ drug therapy
Binding Sites
Carotid Artery, Common
/ pathology
Chemokine CXCL12
/ metabolism
Crystallography, X-Ray
Disease Models, Animal
Drug Design
Drug Evaluation, Preclinical
Endarterectomy, Carotid
Female
Humans
Intramolecular Oxidoreductases
/ antagonists & inhibitors
Macrophage Migration-Inhibitory Factors
/ antagonists & inhibitors
Male
Mice
Mice, Knockout, ApoE
Middle Aged
Peptide Fragments
/ pharmacology
Receptors, CXCR4
/ chemistry
Sialyltransferases
/ metabolism
Signal Transduction
/ drug effects
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
25 11 2020
25 11 2020
Historique:
received:
02
12
2019
accepted:
28
10
2020
entrez:
26
11
2020
pubmed:
27
11
2020
medline:
15
12
2020
Statut:
epublish
Résumé
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
Identifiants
pubmed: 33239628
doi: 10.1038/s41467-020-19764-z
pii: 10.1038/s41467-020-19764-z
pmc: PMC7689490
doi:
Substances chimiques
Antigens, CD
0
CXCL12 protein, human
0
CXCR4 protein, human
0
Chemokine CXCL12
0
Macrophage Migration-Inhibitory Factors
0
Peptide Fragments
0
Receptors, CXCR4
0
Sialyltransferases
EC 2.4.99.-
ST6GAL1 protein, human
EC 2.4.99.1
Intramolecular Oxidoreductases
EC 5.3.-
MIF protein, human
EC 5.3.2.1
Mif protein, mouse
EC 5.3.2.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Video-Audio Media
Langues
eng
Sous-ensembles de citation
IM
Pagination
5981Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
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