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

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.