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  Identification and characterization of novel classes of macrophage migration inhibitory factor (MIF) inhibitors with distinct mechanisms of action.

Ouertatani-Sakouhi, H., El-Turk, F., Fauvet, B., Cho, M. K., Karpinar, D. P., Le Roy, D., et al. (2010). Identification and characterization of novel classes of macrophage migration inhibitory factor (MIF) inhibitors with distinct mechanisms of action. Journal of Biological Chemistry, 285(34), 26581-26598. doi:10.1074/jbc.M110.113951.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0011-F061-8 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-D0ED-2
Genre: Journal Article

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 Creators:
Ouertatani-Sakouhi, H., Author
El-Turk, F., Author
Fauvet, B., Author
Cho, M. K., Author
Karpinar, D. P., Author
Le Roy, D., Author
Dewor, M., Author
Roger, T., Author
Bernhagen, J., Author
Calandra, T., Author
Zweckstetter, M.1, Author              
Lashuel, H. A., Author
Affiliations:
1Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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Free keywords: Biophysics; Covalent Regulation; Enzyme Inhibitors; Inflammation; Protein Structure; Ebselen; Disulfide Mutant; Macrophage Migration Inhibitory Factor; Suicide Inhibitors
 Abstract: Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is considered an attractive therapeutic target in multiple inflammatory and autoimmune disorders. In addition to its known biologic activities, MIF can also function as a tautomerase. Several small molecules have been reported to be effective inhibitors of MIF tautomerase activity in vitro. Herein we employed a robust activity-based assay to identify different classes of novel inhibitors of the catalytic and biological activities of MIF. Several novel chemical classes of inhibitors of the catalytic activity of MIF with IC50 values in the range of 0.2–15.5 μm were identified and validated. The interaction site and mechanism of action of these inhibitors were defined using structure-activity studies and a battery of biochemical and biophysical methods. MIF inhibitors emerging from these studies could be divided into three categories based on their mechanism of action: 1) molecules that covalently modify the catalytic site at the N-terminal proline residue, Pro1; 2) a novel class of catalytic site inhibitors; and finally 3) molecules that disrupt the trimeric structure of MIF. Importantly, all inhibitors demonstrated total inhibition of MIF-mediated glucocorticoid overriding and AKT phosphorylation, whereas ebselen, a trimer-disrupting inhibitor, additionally acted as a potent hyperagonist in MIF-mediated chemotactic migration. The identification of biologically active compounds with known toxicity, pharmacokinetic properties, and biological activities in vivo should accelerate the development of clinically relevant MIF inhibitors. Furthermore, the diversity of chemical structures and mechanisms of action of our inhibitors makes them ideal mechanistic probes for elucidating the structure-function relationships of MIF and to further determine the role of the oligomerization state and catalytic activity of MIF in regulating the function(s) of MIF in health and disease.

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Language(s): eng - English
 Dates: 2010-08-20
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1074/jbc.M110.113951
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Title: Journal of Biological Chemistry
Source Genre: Journal
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Pages: - Volume / Issue: 285 (34) Sequence Number: - Start / End Page: 26581 - 26598 Identifier: ISSN: 0021-9258