@article{5e22b6d876a24a58bb464b647e32eac1,
title = "Designed CXCR4 mimic acts as a soluble chemokine receptor that blocks atherogenic inflammation by agonist-specific targeting",
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. 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.",
keywords = "MIGRATION-INHIBITORY FACTOR, CELL-DERIVED FACTOR-1-ALPHA, FACTOR MIF, CYTOKINE, ATHEROSCLEROSIS, EXPRESSION, BINDING, CXCL12, MOUSE, LIGAND",
author = "Christos Kontos and {El Bounkari}, Omar and Christine Krammer and Dzmitry Sinitski and Kathleen Hille and Chunfang Zan and Guangyao Yan and Sijia Wang and Ying Gao and Markus Brandhofer and Megens, {Remco T. A.} and Adrian Hoffmann and Jessica Pauli and Yaw Asare and Simona Gerra and Priscila Bourilhon and Lin Leng and Hans-Henning Eckstein and Kempf, {Wolfgang E.} and Jaroslav Pelisek and Ozgun Gokce and Lars Maegdefessel and Richard Bucala and Martin Dichgans and Christian Weber and Aphrodite Kapurniotu and Juergen Bernhagen",
note = "Funding Information: This work was supported by Deutsche Forschungsgemeinschaft (DFG) grant SFB1123-A3 to J.B. and A.K., DFG INST 409/209-1 FUGG to J.B., SFB1123-A1 to C.W., SFB1123-Z2 to R.T.A.M., SFB1123-B3 to M.D. and Y.A., SFB1123-B5 to L.M. and by DFG under Germany{\textquoteright}s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) to J.B., C.W., and M.D. C.W. is Van de Laar Professor of Atherosclerosis and R.B. is Waldemar Von Zedtwitz Professor of Medicine and supported by NIH R01 AR049610. A.H. is supported by a Metiphys scholarship of LMU Munich. We thank Dr. Philipp von Hundelshausen and Dr. Xavier Blanchet for providing recombinant CXCL12, Dr. Robert Kleemann for plaque specimens from Ldlr−/−and Ldlr−/− Mif−/− mice, Mathias Holzner for assistance with the chemotaxis experiments, Carolus Therapeutics, Inc. for providing MIF peptide fragments, Dr. Thomas Hennes for cloning MIF(10xAla), and Simon Besson-Girard for help with the statistical analyses. We thank Dr. Sophie Brameyer and the Biophysics Core Facility at the School of Biology of LMU Munich and Prof. Michaela Smolle at the LMU Biomedical Center for usage of their MST instruments. We thank the mass spectrometry facilities of Technische Universit{\"a}t M{\"u}nchen (TUM) (Department of Chemistry, Garching; Bavarian Center for Biomolecular Mass Spectrometry, BayBioMS, Freising) for mass spectrometric measurements, Dr. Joana Viola-S{\"o}hnlein for help with the Luminex instrument, and Dr. Dorothee Atzler for advice regarding the pharmacokinetic experiments. Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2020",
month = dec,
day = "25",
doi = "10.1038/s41467-020-19764-z",
language = "English",
volume = "11",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}