Allosteric Inhibitors of Macrophage Migration Inhibitory Factor (MIF) Interfere with Apoptosis-Inducing Factor (AIF) Co-Localization to Prevent Parthanatos

Abstract

Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine and essential signaling protein associated with inflammation and cancers. One of the newly described roles of MIF is binding to apoptosis-inducing factor (AIF) that “brings” cells to death in pathological conditions. The interaction between MIF and AIF and their nuclear translocation stands as a central event in parthanatos. However, classical competitive MIF tautomerase inhibitors do not interfere with MIF functions in parthanatos. In this study, we employed a pharmacophore-switch to provide allosteric MIF tautomerase inhibitors that interfere with the MIF/AIF co-localization. Synthesis and screening of a focused compound collection around the 1,2,3-triazole core enabled identification of the allosteric tautomerase MIF inhibitor 6y with low micromolar potency (IC50 = 1.7 ± 0.1 μM). This inhibitor prevented MIF/AIF nuclear translocation and protects cells from parthanatos. These findings indicate that alternative modes to target MIF hold promise to investigate MIF function in parthanatos-mediated diseases.

Mechanistic insight into the mode of inhibition of dietary flavonoids; targeting macrophage migration inhibitory factor

“…Moreover, the protein under discussion also executes the phenylpyruvate tautomerase activity, catalyzing the tautomerization of phenylpyruvate tautomerase and D-dopachrome, dependent on the distinctive proline residue (Pro1) from the N-terminal of the monomer. Thus, Pro1 is critical for the interaction of MIF with other receptors on the cell surface ( Yang et al, 2021 ; Chen et al, 2023 ). However, uncertainties exist concerning the correlation between enzymatic activity and physiological role.…”