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 journalArticleAcademicpeer-review

4 Citations (Web of Science)

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 languageEnglish
Pages (from-to)1012-1019
Number of pages8
JournalChembiochem
Volume22
Issue number6
Early online date30 Nov 2020
DOIs
Publication statusPublished - 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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