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

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.