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

Détails

ID Serval
serval:BIB_C6DDF1D68B64
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Identification and characterization of novel classes of macrophage migration inhibitory factor (MIF) inhibitors with distinct mechanisms of action.
Périodique
Journal of Biological Chemistry
Auteur(s)
Ouertatani-Sakouhi H., El-Turk F., Fauvet B., Cho M.K., Pinar Karpinar D., Le Roy D., Dewor M., Roger T., Bernhagen J., Calandra T., Zweckstetter M., Lashuel H.A.
ISSN
1083-351X[electronic], 0021-9258[linking]
Statut éditorial
Publié
Date de publication
2010
Volume
285
Numéro
34
Pages
26581-26598
Langue
anglais
Résumé
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 IC(50) values in the range of 0.2-15.5 microm 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, Pro(1); 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.
Mots-clé
d-dopachrome tautomerase, antiinflammatory agents, glutathione-peroxidase, inflammatory activity, rheumatoid-arthritis, enzymatic-activity, molecular-cloning, crystal-structure, potential role, severe sepsis,
Pubmed
Web of science
Open Access
Oui
Création de la notice
02/09/2010 12:19
Dernière modification de la notice
20/08/2019 16:42
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