Discovery of fusidic acid derivatives as novel STING inhibitors for treatment of sepsis

Sepsis promising treatment target for sepsis. In this study, we report the design and synthesis of a new series of fusidic acid derivatives. Among the synthesized derivatives, the promising compound 30 inhibited lipopolysaccharide (LPS)-induced nitric oxide production in macrophages with an IC50 of 1.15 mu M. Compound 30 was then identified as a STING inhibitor that suppressed LPS-induced inflammatory responses and inhibited the abnormal activation of the TBK1, IRF3, and NF-kappa B signaling pathways by targeting STING. In vivo treatment with compound 30 significantly inhibited the inflammatory response and ameliorated the histopathological changes of the liver, and the mechanism of its anti-inflammatory effect in vivo was the same as that in vitro. Our studies identified compound 30 as a potent STING inhibitor, laying the groundwork for future drug development of anti-inflammatory agents for the treatment of sepsis.

Automated summary

In this study, a new series of fusidic acid derivatives were designed and synthesized, and compound 30 was identified as a potent STING inhibitor with the ability to suppress LPS-induced inflammatory responses. In vivo experiments confirmed the anti-inflammatory effect of compound 30 and its potential for treating sepsis. This study lays the groundwork for the future development of anti-inflammatory agents for sepsis treatment.