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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
25
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pubmed:dateCreated |
2010-6-23
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pubmed:databankReference |
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
1091-6490
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pubmed:author |
pubmed-author:BucalaRichardR,
pubmed-author:CappelloMichaelM,
pubmed-author:ChoYoonsangY,
pubmed-author:CrichlowGregg VGV,
pubmed-author:GaetaFedericoF,
pubmed-author:GrossMattM,
pubmed-author:HodsdonMichael EME,
pubmed-author:JohnsonKirkK,
pubmed-author:LüZ BZB,
pubmed-author:LengLinL,
pubmed-author:LolisElias JEJ,
pubmed-author:VermeireJon JJJ
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pubmed:issnType |
Electronic
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pubmed:day |
22
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pubmed:volume |
107
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
11313-8
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pubmed:dateRevised |
2011-11-10
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pubmed:meshHeading |
pubmed-meshheading:20534506-Allosteric Site,
pubmed-meshheading:20534506-Binding Sites,
pubmed-meshheading:20534506-Catalysis,
pubmed-meshheading:20534506-Chemotaxis,
pubmed-meshheading:20534506-Crystallography, X-Ray,
pubmed-meshheading:20534506-Cytokines,
pubmed-meshheading:20534506-Humans,
pubmed-meshheading:20534506-Inflammation,
pubmed-meshheading:20534506-Intramolecular Oxidoreductases,
pubmed-meshheading:20534506-Kinetics,
pubmed-meshheading:20534506-Macrophage Migration-Inhibitory Factors,
pubmed-meshheading:20534506-Phenylpyruvic Acids,
pubmed-meshheading:20534506-Platelet Aggregation Inhibitors,
pubmed-meshheading:20534506-Protein Binding,
pubmed-meshheading:20534506-Pyridines,
pubmed-meshheading:20534506-Spectrometry, Fluorescence
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pubmed:year |
2010
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pubmed:articleTitle |
Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast.
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pubmed:affiliation |
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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