A MIF-Derived Cyclopeptide that Inhibits MIF Binding and Atherogenic Signaling via the Chemokine Receptor CXCR2

Christine Krammer; Christos Kontos; Manfred Dewor; Kathleen Hille; Beatrice Dalla Volta; Omar El Bounkari; Karin Tas; Dzmitry Sinitski; Markus Brandhofer; Remco T. A. Megens; Christian Weber; Joshua R. Schultz; Jurgen Bernhagen; Aphrodite Kapurniotu

doi:10.1002/cbic.202000574

A MIF-Derived Cyclopeptide that Inhibits MIF Binding and Atherogenic Signaling via the Chemokine Receptor CXCR2

Christine Krammer
, Christos Kontos
, Manfred Dewor
, Kathleen Hille
, Beatrice Dalla Volta
, Omar El Bounkari
, Karin Tas
, Dzmitry Sinitski
, Markus Brandhofer
, Remco T. A. Megens
, Christian Weber
, Joshua R. Schultz
, Jurgen Bernhagen^*
, Aphrodite Kapurniotu^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine and atypical chemokine with a key role in inflammatory diseases including atherosclerosis. Key atherogenic functions of MIF are mediated by noncognate interaction with the chemokine receptor CXCR2. The MIF N-like loop comprising the sequence 47-56 is an important structural determinant of the MIF/CXCR2 interface and MIF(47-56) blocks atherogenic MIF activities. However, the mechanism and critical structure-activity information within this sequence have remained elusive. Here, we show that MIF(47-56) directly binds to CXCR2 to compete with MIF receptor activation. By using alanine scanning, essential and dispensable residues were identified. Moreover, MIF(cyclo10), a designed cyclized variant of MIF(47-56), inhibited key inflammatory and atherogenic MIF activities in vitro and in vivo/ex vivo, and exhibited strongly improved resistance to proteolytic degradation in human plasma in vitro, thus suggesting that it could serve as a promising basis for MIF-derived anti-atherosclerotic peptides.

Original language	English
Pages (from-to)	1012-1019
Number of pages	8
Journal	Chembiochem
Volume	22
Issue number	6
Early online date	30 Nov 2020
DOIs	https://doi.org/10.1002/cbic.202000574
Publication status	Published - 16 Mar 2021

Keywords

alanine scanning
atherosclerosis
chemokine receptors
cyclic peptides
macrophage migration inhibitory factor
INTERNATIONAL UNION
ATHEROSCLEROSIS
MECHANISMS
DISEASE
NOMENCLATURE
BIOACTIVITY
AFFINITY
FAMILY
LIGAND
STATE

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10.1002/cbic.202000574Licence: CC BY

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Krammer, C., Kontos, C., Dewor, M., Hille, K., Dalla Volta, B., El Bounkari, O., Tas, K., Sinitski, D., Brandhofer, M., Megens, R. T. A., Weber, C., Schultz, J. R., Bernhagen, J., & Kapurniotu, A. (2021). A MIF-Derived Cyclopeptide that Inhibits MIF Binding and Atherogenic Signaling via the Chemokine Receptor CXCR2. Chembiochem, 22(6), 1012-1019. https://doi.org/10.1002/cbic.202000574

@article{8ea35379af84432d8cb2bfe28425e12d,

title = "A MIF-Derived Cyclopeptide that Inhibits MIF Binding and Atherogenic Signaling via the Chemokine Receptor CXCR2",

abstract = "Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine and atypical chemokine with a key role in inflammatory diseases including atherosclerosis. Key atherogenic functions of MIF are mediated by noncognate interaction with the chemokine receptor CXCR2. The MIF N-like loop comprising the sequence 47-56 is an important structural determinant of the MIF/CXCR2 interface and MIF(47-56) blocks atherogenic MIF activities. However, the mechanism and critical structure-activity information within this sequence have remained elusive. Here, we show that MIF(47-56) directly binds to CXCR2 to compete with MIF receptor activation. By using alanine scanning, essential and dispensable residues were identified. Moreover, MIF(cyclo10), a designed cyclized variant of MIF(47-56), inhibited key inflammatory and atherogenic MIF activities in vitro and in vivo/ex vivo, and exhibited strongly improved resistance to proteolytic degradation in human plasma in vitro, thus suggesting that it could serve as a promising basis for MIF-derived anti-atherosclerotic peptides.",

keywords = "alanine scanning, atherosclerosis, chemokine receptors, cyclic peptides, macrophage migration inhibitory factor, INTERNATIONAL UNION, ATHEROSCLEROSIS, MECHANISMS, DISEASE, NOMENCLATURE, BIOACTIVITY, AFFINITY, FAMILY, LIGAND, STATE",

author = "Christine Krammer and Christos Kontos and Manfred Dewor and Kathleen Hille and \{Dalla Volta\}, Beatrice and \{El Bounkari\}, Omar and Karin Tas and Dzmitry Sinitski and Markus Brandhofer and Megens, \{Remco T. A.\} and Christian Weber and Schultz, \{Joshua R.\} and Jurgen Bernhagen and Aphrodite Kapurniotu",

note = "Funding Information: This work was supported by Deutsche Forschungsgemeinschaft (DFG) grant SFB1123‐A3 to A.K. and J.B., SFB1123‐A1 to C.W., SFB1123‐Z1 to R.T.A.M., and by DFG under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC2145 SyNergy ID 390857198) to J.B. and C.W.; J.B. and the MPM facility at the Chair of Vascular Biology at LMU University Hospital received funds from DFG under INST 409/209 FUGG. C.W. is Van de Laar Professor of Atherosclerosis. We thank Carolus Therapeutics, Inc., for providing MIF‐derived peptides and Simona Gerra, Michael Lacy, and Priscila Bourilhon for technical assistance with the preparation of recombinant MIF. We thank Dr. Hongqi Lue and Dr. Thomas Cho for valuable advice and discussions, and the mass spectrometry facility of Technische Universit{\"a}t M{\"u}nchen (TUM; Bavarian Center for Biomolecular Mass Spectrometry, BayBioMS, Freising) for access to mass spectrometry. Open access funding enabled and organized by Projekt DEAL. Publisher Copyright: {\textcopyright} 2020 The Authors. ChemBioChem published by Wiley-VCH GmbH",

year = "2021",

month = mar,

day = "16",

doi = "10.1002/cbic.202000574",

language = "English",

volume = "22",

pages = "1012--1019",

journal = "Chembiochem",

issn = "1439-4227",

publisher = "John Wiley \& Sons Inc.",

number = "6",

}

Krammer, C, Kontos, C, Dewor, M, Hille, K, Dalla Volta, B, El Bounkari, O, Tas, K, Sinitski, D, Brandhofer, M, Megens, RTA, Weber, C, Schultz, JR, Bernhagen, J & Kapurniotu, A 2021, 'A MIF-Derived Cyclopeptide that Inhibits MIF Binding and Atherogenic Signaling via the Chemokine Receptor CXCR2', Chembiochem, vol. 22, no. 6, pp. 1012-1019. https://doi.org/10.1002/cbic.202000574

TY - JOUR

T1 - A MIF-Derived Cyclopeptide that Inhibits MIF Binding and Atherogenic Signaling via the Chemokine Receptor CXCR2

AU - Krammer, Christine

AU - Kontos, Christos

AU - Dewor, Manfred

AU - Hille, Kathleen

AU - Dalla Volta, Beatrice

AU - El Bounkari, Omar

AU - Tas, Karin

AU - Sinitski, Dzmitry

AU - Brandhofer, Markus

AU - Megens, Remco T. A.

AU - Weber, Christian

AU - Schultz, Joshua R.

AU - Bernhagen, Jurgen

AU - Kapurniotu, Aphrodite

N1 - Funding Information: This work was supported by Deutsche Forschungsgemeinschaft (DFG) grant SFB1123‐A3 to A.K. and J.B., SFB1123‐A1 to C.W., SFB1123‐Z1 to R.T.A.M., and by DFG under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC2145 SyNergy ID 390857198) to J.B. and C.W.; J.B. and the MPM facility at the Chair of Vascular Biology at LMU University Hospital received funds from DFG under INST 409/209 FUGG. C.W. is Van de Laar Professor of Atherosclerosis. We thank Carolus Therapeutics, Inc., for providing MIF‐derived peptides and Simona Gerra, Michael Lacy, and Priscila Bourilhon for technical assistance with the preparation of recombinant MIF. We thank Dr. Hongqi Lue and Dr. Thomas Cho for valuable advice and discussions, and the mass spectrometry facility of Technische Universität München (TUM; Bavarian Center for Biomolecular Mass Spectrometry, BayBioMS, Freising) for access to mass spectrometry. Open access funding enabled and organized by Projekt DEAL. Publisher Copyright: © 2020 The Authors. ChemBioChem published by Wiley-VCH GmbH

PY - 2021/3/16

Y1 - 2021/3/16

N2 - Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine and atypical chemokine with a key role in inflammatory diseases including atherosclerosis. Key atherogenic functions of MIF are mediated by noncognate interaction with the chemokine receptor CXCR2. The MIF N-like loop comprising the sequence 47-56 is an important structural determinant of the MIF/CXCR2 interface and MIF(47-56) blocks atherogenic MIF activities. However, the mechanism and critical structure-activity information within this sequence have remained elusive. Here, we show that MIF(47-56) directly binds to CXCR2 to compete with MIF receptor activation. By using alanine scanning, essential and dispensable residues were identified. Moreover, MIF(cyclo10), a designed cyclized variant of MIF(47-56), inhibited key inflammatory and atherogenic MIF activities in vitro and in vivo/ex vivo, and exhibited strongly improved resistance to proteolytic degradation in human plasma in vitro, thus suggesting that it could serve as a promising basis for MIF-derived anti-atherosclerotic peptides.

AB - Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine and atypical chemokine with a key role in inflammatory diseases including atherosclerosis. Key atherogenic functions of MIF are mediated by noncognate interaction with the chemokine receptor CXCR2. The MIF N-like loop comprising the sequence 47-56 is an important structural determinant of the MIF/CXCR2 interface and MIF(47-56) blocks atherogenic MIF activities. However, the mechanism and critical structure-activity information within this sequence have remained elusive. Here, we show that MIF(47-56) directly binds to CXCR2 to compete with MIF receptor activation. By using alanine scanning, essential and dispensable residues were identified. Moreover, MIF(cyclo10), a designed cyclized variant of MIF(47-56), inhibited key inflammatory and atherogenic MIF activities in vitro and in vivo/ex vivo, and exhibited strongly improved resistance to proteolytic degradation in human plasma in vitro, thus suggesting that it could serve as a promising basis for MIF-derived anti-atherosclerotic peptides.

KW - alanine scanning

KW - atherosclerosis

KW - chemokine receptors

KW - cyclic peptides

KW - macrophage migration inhibitory factor

KW - INTERNATIONAL UNION

KW - ATHEROSCLEROSIS

KW - MECHANISMS

KW - DISEASE

KW - NOMENCLATURE

KW - BIOACTIVITY

KW - AFFINITY

KW - FAMILY

KW - LIGAND

KW - STATE

U2 - 10.1002/cbic.202000574

DO - 10.1002/cbic.202000574

M3 - Article

C2 - 33125165

SN - 1439-4227

VL - 22

SP - 1012

EP - 1019

JO - Chembiochem

JF - Chembiochem

IS - 6

ER -

A MIF-Derived Cyclopeptide that Inhibits MIF Binding and Atherogenic Signaling via the Chemokine Receptor CXCR2

Abstract

Keywords

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