Treatment of Sepsis Pathogenesis with High Mobility Group Box Protein 1-Regulating Anti-inflammatory Agents.

Abstract

Sepsis is one of the major causes of death worldwide when associated with multiple organ failure. However, there is a critical lack of adequate sepsis therapies because of its diverse patterns of pathogenesis. The pro-inflammatory cytokine cascade mediates sepsis pathogenesis, and high mobility group box proteins (HMGBs) play an important role as late-stage cytokines. We previously reported the small-molecule modulator, inflachromene (1d), which inhibits the release of HMGBs and, thereby, reduces the production of pro-inflammatory cytokines. In this context, we intraperitoneally administered 1d to a cecal ligation and puncture (CLP)-induced mouse model of sepsis and confirmed that it successfully ameliorated sepsis pathogenesis. On the basis of a structure-activity relationship study, we discovered new candidate compounds, 2j and 2l, with improved therapeutic efficacy in vivo. Therefore, our study clearly demonstrates that the regulation of HMGB1 release using small molecules is a promising strategy for the treatment of sepsis.

• Authors: Wansang Cho, Ja Young Koo, Yeonju Park, Keunhee Oh, Sanghee Lee, Jin-Sook Song, Myung Ae Bae, Donghyun Lim, Dong-Sup Lee, Seung Bum Park
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 60 Issue 1 Pg. 170-179 (01 12 2017) ISSN: 1520-4804 [Electronic] United States
• PMID: 28001381 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• HMGB1 Protein
• Interleukin-6

Topics

• Animals
• Anti-Inflammatory Agents (pharmacokinetics, pharmacology, therapeutic use)
• Disease Models, Animal
• HMGB1 Protein (antagonists & inhibitors, metabolism)
• Interleukin-6 (metabolism)
• Mice
• Microsomes, Liver (drug effects)
• Sepsis (drug therapy)
• Signal Transduction
• Structure-Activity Relationship