Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast.
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.
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA.
Yoonsang
Y
Cho
Gregg V
GV
Crichlow
Jon J
JJ
Vermeire
Lin
L
Leng
Xin
X
Du
Michael E
ME
Hodsdon
Richard
R
Bucala
Michael
M
Cappello
Matt
M
Gross
Federico
F
Gaeta
Kirk
K
Johnson
Elias J
EJ
Lolis
D000495:Allosteric Site; D001665:Binding Sites; D002384:Catalysis; D002633:Chemotaxis; D018360:Crystallography, X-Ray / Q000379:methods; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D019746:Intramolecular Oxidoreductases / Q000737:chemistry; D007700:Kinetics; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D010667:Phenylpyruvic Acids / Q000737:chemistry; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry*; D013050:Spectrometry, Fluorescence / Q000379:methods; D007212:Indolizines; D011720:Pyrazoles
D016207:Cytokines; D019746:Intramolecular Oxidoreductases; D008263:Macrophage Migration-Inhibitory Factors; D010667:Phenylpyruvic Acids; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; C010590:4-hydroxyphenylpyruvic acid; C022346:phenylpyruvate tautomerase; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles