Abstract
Abstract AV411 (Ibudilast) is an anti-inflammatory 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 non-selective inhibitor of various phosphodiesterases (PDEs) and has varied anti-inflammatory 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 inhibitors rolipram, theophylline, isobutylmethylxanthine (IBMX), cilostazol, arofylline, AV411 and its PDE-inhibition compromised analog AV1013 inhibit the catalytic and chemotactic functions of the pro-inflammatory protein, macrophage migration inhibitory factor (MIF). Enzymatic analysis indicates that these compounds are non-competitive inhibitors of the p-hydroxyphenylpyruvate (HPP) tautomerase activity of MIF. The allosteric binding site of AV411 and AV1013 is identified by NMR and X-ray crystallography, and the structural basis of inhibition is reported using the crystal structure of the MIF/AV1013/HPP ternary complex.
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