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A MIF‐Derived Cyclopeptide that Inhibits MIF Binding and Atherogenic Signaling via the Chemokine Receptor CXCR2
Author(s) -
Krammer Christine,
Kontos Christos,
Dewor Manfred,
Hille Kathleen,
Dalla Volta Beatrice,
El Bounkari Omar,
Taş Karin,
Sinitski Dzmitry,
Brandhofer Markus,
Megens Remco T. A.,
Weber Christian,
Schultz Joshua R.,
Bernhagen Jürgen,
Kapurniotu Aphrodite
Publication year - 2021
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.202000574
Subject(s) - macrophage migration inhibitory factor , cxc chemokine receptors , alanine scanning , chemokine , chemokine receptor , receptor , microbiology and biotechnology , in vivo , cytokine , signal transduction , chemistry , biology , immunology , biochemistry , gene , mutant , mutagenesis
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.