Macrophage Migration Inhibitory Factor and the Discovery of Tautomerase Inhibitors

Abstract

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine released from T-cells and macrophages, and is a key molecule in inflammation. Although a detailed understanding of the biological functions of MIF has not yet been found, it is known that MIF catalyzes the tautomerization of phenylpyruvate and a non-physiological molecule, D-dopachrome. A potent tautomerase inhibitor would be expected, as a validation tool, to shed light on role of MIF activity and the relationship between its biological and enzymatic activity. Such tautomerase inhibitors would be useful in the treatment of MIF-related diseases, such as sepsis, acute respiratory distress syndrome (ARDS), asthma, atopic dermatitis, rheumatoid arthritis (RA), nephropathy and tumors. In this review, we have focused on (1) the biological and enzymatic activities of MIF, (2) the discovery of novel, drug-like tautomerase inhibitors of MIF using a structure-based computer-assisted search, and (3) a crystallographic and molecular modeling study of the MIF-tautomerase inhibitor complexes (A review with 133 references).

A Novel Allosteric Inhibitor of Macrophage Migration Inhibitory Factor (MIF)

“…Elevated circulating levels of MIF have been observed in rheumatoid arthritis, atherosclerosis, asthma, lupus, diabetes, colitis, sepsis, cancer, and cardiovascular and infectious diseases (15)(16)(17)(18)(19)(20). Genetic evidence further supports the involvement of MIF in disease.…”

Proteomic changes associated with diabetes in the BB-DP rat

“…3-Oxo-5-␤-steroid 4-dehydrogenase is necessary in bile acid synthesis (31) and as such may have a role in the hypercholesterolemia that accompanies diabetes. D-Dopachrome tautomerase was downregulated in diabetes and is an inflammatory mediator important in T cell and macrophage migration inhibition (47,63) with no established role in diabetes beyond that ketones are effective inhibitors of this enzyme (19). Liver calcium/calmodulin-dependent 3Ј,5Ј-cyclic nucleotide phosphodiesterase 1C (CDCDP) was significantly downregulated in diabetes, suggesting a modification of the calcium signaling/handling pathways in diabetic liver as described for the heart.…”

Identification of Iguratimod as an Inhibitor of Macrophage Migration Inhibitory Factor (MIF) with Steroid-sparing Potential

“…This site has been exploited for the design and high throughput screening of small molecule inhibitors with disease-modifying potential in multiple inflammatory states (31,(35)(36)(37)(38). Using the dopachrome tautomerase assay as a foundation, research groups have discovered multiple classes of reversible MIF inhibitors, including isoxazolines (27,36,39,40), pyrimidazoles (41), coumarin and chromene analogs (42,43), and aromatic amino acid Schiff bases (44). In addition, multiple individual compounds of interest have been identified; notable among these are the Land D-isomers of the metabolic hormone T 4 , the former of which may function as an endogenous ligand of MIF (45).…”