A small molecule binding HMGB1 and HMGB2 inhibits microglia-mediated neuroinflammation

Sanghee Lee; Youngpyo Nam; Ja Young Koo; Donghyun Lim; Jongmin Park; Jiyeon Ock; Jaehong Kim; Kyoungho Suk; Seung Bum Park

doi:10.1038/nchembio.1669

A small molecule binding HMGB1 and HMGB2 inhibits microglia-mediated neuroinflammation

Nat Chem Biol. 2014 Dec;10(12):1055-60. doi: 10.1038/nchembio.1669. Epub 2014 Oct 12.

Authors

Sanghee Lee¹, Youngpyo Nam², Ja Young Koo¹, Donghyun Lim³, Jongmin Park¹, Jiyeon Ock², Jaehong Kim², Kyoungho Suk², Seung Bum Park⁴

Affiliations

¹ Department of Chemistry, Seoul National University, Seoul, Korea.
² Department of Pharmacology, Brain Science and Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Korea.
³ Department of Biophysics and Chemical Biology/N-Bio Institute, Seoul National University, Seoul, Korea.
⁴ 1] Department of Chemistry, Seoul National University, Seoul, Korea. [2] Department of Biophysics and Chemical Biology/N-Bio Institute, Seoul National University, Seoul, Korea.

PMID: 25306442
DOI: 10.1038/nchembio.1669

Abstract

Because of the critical role of neuroinflammation in various neurological diseases, there are continuous efforts to identify new therapeutic targets as well as new therapeutic agents to treat neuroinflammatory diseases. Here we report the discovery of inflachromene (ICM), a microglial inhibitor with anti-inflammatory effects. Using the convergent strategy of phenotypic screening with early stage target identification, we show that the direct binding target of ICM is the high mobility group box (HMGB) proteins. Mode-of-action studies demonstrate that ICM blocks the sequential processes of cytoplasmic localization and extracellular release of HMGBs by perturbing its post-translational modification. In addition, ICM effectively downregulates proinflammatory functions of HMGB and reduces neuronal damage in vivo. Our study reveals that ICM suppresses microglia-mediated inflammation and exerts a neuroprotective effect, demonstrating the therapeutic potential of ICM in neuroinflammatory diseases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / drug effects*
Brain / immunology
Brain / metabolism
Brain / pathology
Cell Line
Coculture Techniques
Gene Expression
HMGB1 Protein / genetics
HMGB1 Protein / immunology*
HMGB1 Protein / metabolism
HMGB2 Protein / genetics
HMGB2 Protein / immunology*
HMGB2 Protein / metabolism
Heterocyclic Compounds, 4 or More Rings / pharmacology*
Inflammation / chemically induced
Inflammation / immunology
Inflammation / pathology
Inflammation / prevention & control
Lipopolysaccharides
Male
Mice
Mice, Inbred C57BL
Microglia / drug effects*
Microglia / immunology
Microglia / pathology
Neuroimmunomodulation
Neurons / drug effects*
Neurons / immunology
Neurons / pathology
Neuroprotective Agents / pharmacology*
Protein Binding
Protein Processing, Post-Translational*
Tumor Necrosis Factor-alpha / biosynthesis
Tumor Necrosis Factor-alpha / immunology

Substances

HMGB1 Protein
HMGB1 protein, mouse
HMGB2 Protein
Heterocyclic Compounds, 4 or More Rings
Lipopolysaccharides
Neuroprotective Agents
Tumor Necrosis Factor-alpha
inflachromene