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A MIF-derived cyclopeptide that inhibits MIF binding and atherogenic signaling via the chemokine receptor CXCR2.

Chembiochem. 2020 Oct 30. doi: 10.1002/cbic.202000574. Epub ahead of print. PMID: 33125165.

Authors/Editors: Krammer C, Kontos C, Dewor M, Hille K, Dalla Volta B, El Bounkari O, Taş K, Sinitski D, Brandhofer M, Megens RTA, Weber C, Schultz JR, Bernhagen J, Kapurniotu A.
Publication Date: 2020

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 via non-cognate interaction with the chemokine receptor CXCR2. The MIF N-like loop comprising 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 inflamma-tory and atherogenic MIF activities in vitro and in vivo / ex vivo , and exhibited strongly improved resistance to proteolytic degradation in human plasma in vitro , sugges-ting that it could serve as a promising basis for MIF-derived anti-atherosclerotic peptides.

Keywords: chemokine; cyclic peptide; cytokine; inflammatory and cardiovascular diseases; macrophage migration inhibitory factor.

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