Crystallographic and Receptor Binding Characterization of Plasmodium falciparum Macrophage Migration Inhibitory Factor Complexed to Two Potent Inhibitors

We report the crystal structures of two inhibitors of Plasmodium falciparum macrophage migration inhibitory factor (PfMIF) with nanomolar K i’s, analyze their interactions with the active site of PfMIF, and provide explanations regarding their selectivity of PfMIF versus human MIF. These inhibitors...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2014-10, Vol.57 (20), p.8652-8656
Main Authors: Pantouris, Georgios, Rajasekaran, Deepa, Baeza Garcia, Alvaro, Ruiz, Victor G., Leng, Lin, Jorgensen, William L., Bucala, Richard, Lolis, Elias J.
Format: Article
Language:English
Subjects:
Antigens, Differentiation, B-Lymphocyte - metabolism
Antimalarials - chemistry
Antimalarials - pharmacology
Brief
Catalytic Domain
Crystallography, X-Ray
Histocompatibility Antigens Class II - metabolism
Humans
Intramolecular Oxidoreductases - chemistry
Intramolecular Oxidoreductases - metabolism
Macrophage Migration-Inhibitory Factors - antagonists & inhibitors
Macrophage Migration-Inhibitory Factors - chemistry
Macrophage Migration-Inhibitory Factors - metabolism
Models, Molecular
Plasmodium falciparum
Protein Stability
Protozoan Proteins - antagonists & inhibitors
Protozoan Proteins - chemistry
Protozoan Proteins - metabolism
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Summary:We report the crystal structures of two inhibitors of Plasmodium falciparum macrophage migration inhibitory factor (PfMIF) with nanomolar K i’s, analyze their interactions with the active site of PfMIF, and provide explanations regarding their selectivity of PfMIF versus human MIF. These inhibitors were also found to selectively inhibit interactions between PfMIF and the human MIF receptor CD74. The results of this study provide the framework for the development of new therapeutics that target PfMIF.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm501168q