Macrophage migration inhibitory factor (MIF) is a pluripotent pro-inflammatory cytokine and is related to acute and chronic inflammatory responses, immune disorders, tumors, and other diseases. In this study, an integrated virtual screening strategy and bioassays were used to search for potent MIF inhibitors. Twelve compounds with better bioactivity than the prototypical MIF-inhibitor ISO-1 (IC50 = 14.41 μM) were identified by an in vitro enzymatic activity assay. Structural analysis revealed that these inhibitors have novel structural scaffolds. Compound 11 was then chosen for further characterization in vitro, and it exhibited marked anti-inflammatory efficacy in LPS-activated BV-2 microglial cells by suppressing the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs). Our findings suggest that MIF may be involved in the regulation of microglial inflammatory activation and that small-molecule MIF inhibitors may serve as promising therapeutic agents for neuroinflammatory diseases.
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This study was supported by the National Natural Science Foundation of China (81703496, 81973334, 31970909, 21173156, 81803430, 81773702, and 81373382), Natural Science Foundation of Hubei Province (2020CFB543), and Natural Science Foundation of Jiangsu Province (BE2019650) and the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD), National Center for International Research (2017B01012), and Inner Mongolia Natural Science Foundation (2019MS08197).
The authors declare no competing interests.
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Zhang, Y., Xu, L., Zhang, Y. et al. Discovery of novel MIF inhibitors that attenuate microglial inflammatory activation by structures-based virtual screening and in vitro bioassays. Acta Pharmacol Sin 43, 1508–1520 (2022). https://doi.org/10.1038/s41401-021-00753-x
- macrophage migration inhibitory factor
- virtual screening
- tautomerase assay
- naive Bayesian classification