ISO-1 binding to the tautomerase active site of MIF inhibits its pro-inflammatory activity and increases survival in severe sepsis.
MIF is a proinflammatory cytokine that has been implicated in the pathogenesis of sepsis, arthritis, and other inflammatory diseases. Antibodies against MIF are effective in experimental models of inflammation, and there is interest in strategies to inhibit its deleterious cytokine activities. Here we identify a mechanism of inhibiting MIF pro-inflammatory activities by targeting MIF tautomerase activity. We designed small molecules to inhibit this tautomerase activity; a lead molecule, "ISO-1 ((S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester)," significantly inhibits the cytokine activity in vitro. Moreover, ISO-1 inhibits tumor necrosis factor release from macrophages isolated from LPStreated wild type mice but has no effect on cytokine release from MIFdeficient macrophages. The therapeutic importance of the MIF inhibition by ISO-1 is demonstrated by the significant protection from sepsis, induced by cecal ligation and puncture in a clinically relevant time frame. These results identify ISO-1 as the first small molecule inhibitor of MIF proinflammatory activities with therapeutic implications and indicate the potential of the MIF active site as a novel target for therapeutic interventions in human sepsis.
Al-Abed
Yousef
Y
Laboratory of Medicinal Chemistry, North Shore-Long Island Jewish Institute for Medical Research, Manhasset, New York 11030, USA. yalabed@nshs.edu
Dabideen
Darrin
D
Aljabari
Bayan
B
Valster
Aline
A
Messmer
Davorka
D
Ochani
Mahendar
M
Tanovic
Mahira
M
Ochani
Kanta
K
Bacher
Michael
M
Nicoletti
Ferdinando
F
Metz
Christine
C
Pavlov
Valentin A
VA
Miller
Edmund J
EJ
Tracey
Kevin J
KJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001665:Binding Sites; D002432:Cecum / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects* / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D019446:Endotoxemia / Q000188:drug therapy / Q000209:etiology; D019746:Intramolecular Oxidoreductases / Q000737:chemistry*; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D011677:Punctures; D018805:Sepsis / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D015996:Survival Rate; D048069:Tumor Necrosis Factors / Q000378:metabolism
C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; D000893:Anti-Inflammatory Agents; D007555:Isoxazoles; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors; D016328:NF-kappa B; D048069:Tumor Necrosis Factors; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase