title: 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.affiliation: CRI Center for Chemical Proteomics, Department of Chemistry, Seoul National University , Seoul 08826, Korea.
authors.forename: Wansang
authors.identifier: 0000-0002-5262-9543
authors.initials: W
authors.lastname: Cho
authors.affiliation: CRI Center for Chemical Proteomics, Department of Chemistry, Seoul National University , Seoul 08826, Korea.
authors.forename: Ja Young
authors.initials: JY
authors.lastname: Koo
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine , Seoul 03080, Korea.
authors.forename: Yeonju
authors.initials: Y
authors.lastname: Park
authors.affiliation: Transplantation Research Institute, Seoul National University College of Medicine , Seoul 03080, Korea.
authors.forename: Keunhee
authors.initials: K
authors.lastname: Oh
authors.affiliation: CRI Center for Chemical Proteomics, Department of Chemistry, Seoul National University , Seoul 08826, Korea.
authors.forename: Sanghee
authors.initials: S
authors.lastname: Lee
authors.affiliation: Korea Bio-Organic Science Division, Korea Research Institute of Chemical Technology , Daejeon, 34114, Korea.
authors.forename: Jin-Sook
authors.initials: JS
authors.lastname: Song
authors.affiliation: Korea Bio-Organic Science Division, Korea Research Institute of Chemical Technology , Daejeon, 34114, Korea.
authors.forename: Myung Ae
authors.initials: MA
authors.lastname: Bae
authors.affiliation: Department of Biophysics and Chemical Biology, Seoul National University , Seoul 08826, Korea.
authors.forename: Donghyun
authors.initials: D
authors.lastname: Lim
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine , Seoul 03080, Korea.
authors.forename: Dong-Sup
authors.initials: DS
authors.lastname: Lee
authors.affiliation: CRI Center for Chemical Proteomics, Department of Chemistry, Seoul National University , Seoul 08826, Korea.|Department of Biophysics and Chemical Biology, Seoul National University , Seoul 08826, Korea.
authors.forename: Seung Bum
authors.identifier: 0000-0003-1753-1433
authors.initials: SB
authors.lastname: Park
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D018805:Sepsis / Q000188:drug therapy*; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D024243:HMGB1 Protein; D015850:Interleukin-6