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

Christos Kontos, Omar El Bounkari, Christine Krammer, Dzmitry Sinitski, Kathleen Hille, Chunfang Zan, Guangyao Yan, Sijia Wang, Ying Gao, Markus Brandhofer, Remco T. A. Megens, Adrian Hoffmann, Jessica Pauli, Yaw Asare, Simona Gerra, Priscila Bourilhon, Lin Leng, Hans-Henning Eckstein, Wolfgang E. Kempf, Jaroslav Pelisek, Ozgun Gokce, Lars Maegdefessel, Richard Bucala, Martin Dichgans, Christian Weber, Aphrodite Kapurniotu () and Jürgen Bernhagen ()
Additional contact information
Christos Kontos: Division of Peptide Biochemistry, TUM School of Life Sciences, Technische Universität München (TUM)
Omar El Bounkari: Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians-Universität (LMU) München
Christine Krammer: Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians-Universität (LMU) München
Dzmitry Sinitski: Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians-Universität (LMU) München
Kathleen Hille: Division of Peptide Biochemistry, TUM School of Life Sciences, Technische Universität München (TUM)
Chunfang Zan: Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians-Universität (LMU) München
Guangyao Yan: Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians-Universität (LMU) München
Sijia Wang: Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians-Universität (LMU) München
Ying Gao: Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians-Universität (LMU) München
Markus Brandhofer: Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians-Universität (LMU) München
Remco T. A. Megens: Institute for Cardiovascular Prevention, Klinikum der Universität München, Ludwig-Maximilians-Universität (LMU) München
Adrian Hoffmann: Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians-Universität (LMU) München
Jessica Pauli: Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technische Universität München (TUM)
Yaw Asare: Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians-Universität (LMU) München
Simona Gerra: Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians-Universität (LMU) München
Priscila Bourilhon: Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians-Universität (LMU) München
Lin Leng: Yale University School of Medicine
Hans-Henning Eckstein: Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technische Universität München (TUM)
Wolfgang E. Kempf: Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technische Universität München (TUM)
Jaroslav Pelisek: Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technische Universität München (TUM)
Ozgun Gokce: Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians-Universität (LMU) München
Lars Maegdefessel: Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technische Universität München (TUM)
Richard Bucala: Yale University School of Medicine
Martin Dichgans: Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians-Universität (LMU) München
Christian Weber: Institute for Cardiovascular Prevention, Klinikum der Universität München, Ludwig-Maximilians-Universität (LMU) München
Aphrodite Kapurniotu: Division of Peptide Biochemistry, TUM School of Life Sciences, Technische Universität München (TUM)
Jürgen Bernhagen: Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians-Universität (LMU) München

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19764-z

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