Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-06, Vol.107 (25), p.11313-11318
• Main Authors: Cho, Yoonsang, Crichlow, Gregg V., Vermeire, Jon J., Leng, Lin, Du, Xin, Hodsdon, Michael E., Bucala, Richard, Cappello, Michael, Gross, Matt, Gaeta, Federico, Johnson, Kirk, Lolis, Elias J., Petsko, Gregory A.
• Format: Article
• Language: English
• Subjects: Active sites; Allosteric Site; ASTHMA; Atoms; BASIC BIOLOGICAL SCIENCES; Binding Sites; Biochemistry; Biological Sciences; BLOOD; Catalysis; Cells; Chemotaxis; CRYSTALLOGRAPHY; Crystallography, X-Ray - methods; Cytokines - metabolism; Drug therapy; Enzymes; Fluorescence; GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; Human migration; Humans; INFLAMMATION; Intramolecular Oxidoreductases - chemistry; Kinetics; Leukocytes; LYMPHOKINES; Macrophage Migration-Inhibitory Factors - metabolism; MACROPHAGES; Molecules; national synchrotron light source; Neuroglia; Nonsteroidal anti-inflammatory drugs; Pain; Phenylpyruvic Acids - chemistry; PHOSPHODIESTERASES; Platelet Aggregation Inhibitors - pharmacology; Protein Binding; Proteins; Pyridines - chemistry; Spectrometry, Fluorescence - methods
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1002716107

AV411 (ibudilast; 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine) is an antiinflammatory drug that was initially developed for the treatment of bronchial asthma but which also has been used for cerebrovascular and ocular indications. It is a nonselective inhibitor of various phosphodiesterases (PDEs) and has varied antiinflammatory activity. More recently, AV411 has been studied as a possible therapeutic for the treatment of neuropathic pain and opioid withdrawal through its actions on glial cells. As described herein, the PDE inhibitor AV411 and its PDE-inhibition-compromised analog AV1013 inhibit the catalytic and chemotactic functions of the proinflammatory protein, macrophage migration inhibitory factor (MIF). Enzymatic analysis indicates that these compounds are noncompetitive inhibitors of the p-hydroxyphenylpyruvate (HPP) tautomerase activity of MIF and an allosteric binding site of AV411 and AV1013 is detected by NMR. The allosteric inhibition mechanism is further elucidated by X-ray crystallography based on the MIF/AV1013 binary and MIF/AV1013/HPP ternary complexes. In addition, our antibody experiments directed against MIF receptors indicate that CXCR2 is the major receptor for MIF-mediated chemotaxis of peripheral blood mononuclear cells.