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PMID: 20534506 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 107 ·No. 25 ·2010-06-22 ·Pages 11313-8

Cho Y, Crichlow GV, Vermeire JJ, Leng L, Du X, Hodsdon ME, Bucala R, Cappello M, Gross M, Gaeta F, Johnson K, Lolis EJ

Abstract

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.

MeSH Terms
Allosteric Site Binding Sites Catalysis Chemotaxis Crystallography, X-Ray/methods Cytokines/metabolism Humans Inflammation Intramolecular Oxidoreductases/chemistry Kinetics Macrophage Migration-Inhibitory Factors/metabolism Phenylpyruvic Acids/chemistry Platelet Aggregation Inhibitors/pharmacology Protein Binding Pyridines/chemistry Spectrometry, Fluorescence/methods
Chemicals
Cytokines Macrophage Migration-Inhibitory Factors Phenylpyruvic Acids Platelet Aggregation Inhibitors Pyridines 4-hydroxyphenylpyruvic acid Intramolecular Oxidoreductases phenylpyruvate tautomerase ibudilast
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Cho Yoonsang
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA.
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
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1002716107
Published
2010-06-22
Epub
2010-00-08
Pages
11313-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2895110
Subset
IM
Grants
NIAID NIH HHS · R01 AI065029-05 · United States
NIAID NIH HHS · R01 AI065029 · United States
NIAID NIH HHS · AI-082295 · United States
NIAMS NIH HHS · R01 AR049610 · United States
NINDS NIH HHS · T32 NS007136 · United States
NIBIB NIH HHS · P30 EB009998 · United States
NIAID NIH HHS · R01 AI-065029 · United States
NIAID NIH HHS · R01 AI082295 · United States
Databases
PDB
3IJG, 3IJJ
External Links
PubMed source DOI: 10.1073/pnas.1002716107 PMC Full Text View journal details
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