351. A fluorinated analog of ISO-1 blocks the recognition and biological function of MIF and is orally efficacious in a murine model of colitis
- Author
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Pooja Bhatt, Ravindra Dattatraya Gupte, Chandrika B-Rao, Pradip K. Gadekar, Santosh S. Parkale, Sarala Balachandran, Nilesh M. Dagia, Divya V. Kamath, Shaila Srinivasan, Anshu Chetrapal-Kunwar, Koteppa Pari, Julie Bose, Gautam Agarwal, Shruta S. Dadarkar, Somesh Sharma, Noopur Mandrekar, Ram A. Vishwakarma, Atish Rodge, and Lyle C. Fonseca
- Subjects
animal diseases ,Anti-Inflammatory Agents ,Administration, Oral ,chemical and pharmacologic phenomena ,Inflammation ,Pharmacology ,Monocytes ,Cell Line ,Mice ,Drug Delivery Systems ,In vivo ,Oral administration ,otorhinolaryngologic diseases ,Medicine ,Animals ,Humans ,Colitis ,Macrophage Migration-Inhibitory Factors ,ISO 1 ,biology ,business.industry ,Dextran Sulfate ,Active site ,Biological activity ,Isoxazoles ,respiratory system ,medicine.disease ,biological factors ,Intramolecular Oxidoreductases ,Mice, Inbred C57BL ,Disease Models, Animal ,Immunology ,biology.protein ,Quinolines ,Macrophage migration inhibitory factor ,medicine.symptom ,business - Abstract
A promising therapeutic approach to diminish pathological inflammation is to inhibit the synthesis and/or biological activity of macrophage migration inhibitory factor (MIF). Prior studies have shown that intraperitoneal administration of small-molecule inhibitors targeting the catalytic pocket of MIF (e.g., ISO-1) elicits a therapeutic effect in mouse inflammation models. However, it remains to be elucidated whether these tautomerase activity inhibitors block the synthesis and/or biological activity of MIF. In this study, we investigated and compared the activity of representative MIF inhibitors from isoxazole series (fluorinated analog of ISO-1; ISO-F) and substituted quinoline series (compound 7E; 7E). Our results demonstrate that ISO-F is a more potent MIF inhibitor than 7E. Both ISO-F and 7E do not inhibit MIF synthesis but "bind-onto" MIF thereby blocking its recognition. However, in contrast to 7E, ISO-F docks well in the active site of MIF and also has a stronger binding affinity towards MIF. In line with these observations, ISO-F, but not 7E, robustly inhibits the biological function of MIF. Most importantly, ISO-F, when administered orally in a therapeutic regimen, significantly suppresses dextran sulphate sodium (DSS)-induced murine colitis. This study, which provides mechanistic insights into the anti-inflammatory efficacy of ISO-F, is the first documented report of in vivo anti-inflammatory efficacy of a MIF inhibitor upon oral administration. Moreover, the findings from this study reinforce the potential of catalytic site of MIF as a target for eliciting therapeutic effect in inflammatory disorders. Compounds (e.g., ISO-F) that block not only the recognition but also the biological function of MIF are potentially attractive for reducing pathological inflammation.
- Published
- 2008