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

Hajer Ouertatani-Sakouhi, Farah El-Turk, Bruno Fauvet, Min Kyu Cho, Damla Pinar Karpinar, Didier Le Roy, Manfred Dewor, Thierry Roger, Jürgen Bernhagen, Thierry Calandra, Markus Zweckstetter, Hilal A. Lashuel

Research output: Contribution to journalArticle

59 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)26581-26598
Number of pages18
JournalJournal of Biological Chemistry
Volume285
Issue number34
DOIs
Publication statusPublished - 20 Aug 2010
Externally publishedYes

Fingerprint

Macrophage Migration-Inhibitory Factors
Catalyst activity
Catalytic Domain
Bioactivity
Molecules
Proline
Glucocorticoids
Inhibitory Concentration 50
Oligomerization
Phosphorylation
Pharmacokinetics
Cytokines
Toxicity
Assays
Health
Therapeutics
chemotactic inhibitory factor
In Vitro Techniques
ebselen

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Identification and characterization of novel classes of macrophage migration inhibitory factor (MIF) inhibitors with distinct mechanisms of action. / Ouertatani-Sakouhi, Hajer; El-Turk, Farah; Fauvet, Bruno; Cho, Min Kyu; Karpinar, Damla Pinar; Le Roy, Didier; Dewor, Manfred; Roger, Thierry; Bernhagen, Jürgen; Calandra, Thierry; Zweckstetter, Markus; Lashuel, Hilal A.

In: Journal of Biological Chemistry, Vol. 285, No. 34, 20.08.2010, p. 26581-26598.

Research output: Contribution to journalArticle

Ouertatani-Sakouhi, H, El-Turk, F, Fauvet, B, Cho, MK, Karpinar, DP, Le Roy, D, Dewor, M, Roger, T, Bernhagen, J, Calandra, T, Zweckstetter, M & Lashuel, HA 2010, 'Identification and characterization of novel classes of macrophage migration inhibitory factor (MIF) inhibitors with distinct mechanisms of action', Journal of Biological Chemistry, vol. 285, no. 34, pp. 26581-26598. https://doi.org/10.1074/jbc.M110.113951
Ouertatani-Sakouhi, Hajer ; El-Turk, Farah ; Fauvet, Bruno ; Cho, Min Kyu ; Karpinar, Damla Pinar ; Le Roy, Didier ; Dewor, Manfred ; Roger, Thierry ; Bernhagen, Jürgen ; Calandra, Thierry ; Zweckstetter, Markus ; Lashuel, Hilal A. / Identification and characterization of novel classes of macrophage migration inhibitory factor (MIF) inhibitors with distinct mechanisms of action. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 34. pp. 26581-26598.
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