Macrophage migration inhibitory factor (MIF) plays an important role for the recruitment of innate and adaptive immune cells to the place of inflammation. MIF also activates various intracellular signaling pathways in the recruited cells for the release of other cytokines and the expression of cell adhesion molecules. The unique feature as a cytokine, MIF has catalytic (tautomerase) activity, which is yet controversial for its link to the immunological activity of MIF. Despite this controversy, recent studies support that the residues around the active site, not in the active site, play a role in interacting with the receptors. To date, three MIF receptors have been reported: 1) an invariant chain CD74, and CXC cytokine receptors 2) CXCR2 and 3) CXCR4. CD74 does not have tyrosine receptor kinase like signaling domain and requires CD44 that contains a kinase domain. It seems that all these receptors except CD44 directly interact with MIF. These receptors are also known to form hetero-oligomers. Our recent catalytic and chemotactic assays demonstrated that strong competitive inhibitors were not always more potent to the MIF-mediated chemotaxis than weak non-competitive inhibitors. In addition, crystal structures of MIIF inhibitors reveal that free functional groups are exposed to the solvent and available for the interference with receptor binding. In an effort to 1) investigate the interplay between MIF and its receptors and 2) to develop MIF inhibitors as antiinflammatory therapeutics, we identified a structurally diverse set of small molecule inhibitors, performed kinetic and structural characterization. The identified inhibitors will be optimized as drug leads in collaboration with Dr. William Jorgensen (Yale Chemistry Department). Furthermore, ones with good pharmacological properties in vitro will be subject to pharmacokinetics and tested for therapeutic effect in a murine model of rheumatoid arthritis. Outcomes of this proposed research will allow us to better understand MIF action to its receptors and also will provide potential drug leads for the treatment of inflammatory diseases.
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine containing both catalytic and immunological activity, when hyperactive, responsible for inflammatory diseases such as rheumatoid arthritis, lupus, and atherosclerosis. The catalytic site is important to retain immunological activity via interaction with an invariant chain CD74 and G-protein coupled receptors CXCR2 and CXCR4. This proposal seeks to effectively regulate MIF-receptor interaction as well as develop promising antiinflammatory drug leads.
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