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Advances and Insights for Small Molecule Inhibition of Macrophage Migration Inhibitory Factor.

ABSTRACT: Macrophage migration inhibitory factor (MIF) is an upstream regulator of the immune response whose dysregulation is tied to a broad spectrum of inflammatory and proliferative disorders. As its complex signaling pathways and pleiotropic nature have been elucidated, it has become an attractive target for drug discovery. Remarkably, MIF is both a cytokine and an enzyme that functions as a keto-enol tautomerase. Strategies including in silico modeling, virtual screening, high-throughput screening, and screening of anti-inflammatory natural products have led to a large and diverse catalogue of MIF inhibitors as well as some understanding of the structure-activity relationships for compounds binding MIF's tautomerase active site. With possible clinical trials of some MIF inhibitors on the horizon, it is an opportune time to review the literature to seek trends, address inconsistencies, and identify promising new avenues of research.

SUBMITTER: Trivedi-Parmar V

PROVIDER: S-EPMC6311451 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Advances and Insights for Small Molecule Inhibition of Macrophage Migration Inhibitory Factor.

Trivedi-Parmar Vinay V Jorgensen William L WL

Journal of medicinal chemistry 20180604 18

Macrophage migration inhibitory factor (MIF) is an upstream regulator of the immune response whose dysregulation is tied to a broad spectrum of inflammatory and proliferative disorders. As its complex signaling pathways and pleiotropic nature have been elucidated, it has become an attractive target for drug discovery. Remarkably, MIF is both a cytokine and an enzyme that functions as a keto-enol tautomerase. Strategies including in silico modeling, virtual screening, high-throughput screening, a ...[more]

PMID: 29812929

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Project description:Autistic spectrum disorders are childhood neurodevelopmental disorders characterized by social and communicative impairment and repetitive and stereotypical behavior. Macrophage migration inhibitory factor (MIF) is an upstream regulator of innate immunity that promotes monocyte/macrophage-activation responses by increasing the expression of Toll-like receptors and inhibiting activation-induced apoptosis. On the basis of results of previous genetic linkage studies and reported altered innate immune response in autism spectrum disorder, we hypothesized that MIF could represent a candidate gene for autism spectrum disorder or its diagnostic components.Genetic association between autism spectrum disorder and MIF was investigated in 2 independent sets of families of probands with autism spectrum disorder, from the United States (527 participants from 152 families) and Holland (532 participants from 183 families). Probands and their siblings, when available, were evaluated with clinical instruments used for autism spectrum disorder diagnoses. Genotyping was performed for 2 polymorphisms in the promoter region of the MIF gene in both samples sequentially. In addition, MIF plasma analyses were conducted in a subset of Dutch patients from whom plasma was available.There were genetic associations between known functional polymorphisms in the promoter for MIF and autism spectrum disorder-related behaviors. Also, probands with autism spectrum disorder exhibited higher circulating MIF levels than did their unaffected siblings, and plasma MIF concentrations correlated with the severity of multiple autism spectrum disorder symptoms.These results identify MIF as a possible susceptibility gene for autism spectrum disorder. Additional research is warranted on the precise relationship between MIF and the behavioral components of autism spectrum disorder, the mechanism by which MIF contributes to autism spectrum disorder pathogenesis, and the clinical use of MIF genotyping.

Dataset Information

Advances and Insights for Small Molecule Inhibition of Macrophage Migration Inhibitory Factor.

Publications

Advances and Insights for Small Molecule Inhibition of Macrophage Migration Inhibitory Factor.

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