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

ID: ALA5247586

Journal: Eur J Med Chem

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

Authors: Long J, Ying T, Zhang L, Yu T, Wu J, Liu Y, Li X, You G, Zhang L, Bi Y.

Abstract: Sepsis is often caused by systemic inflammatory responses. Stimulator of interferon genes (STING) could be a 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 μM. 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-κB 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.

CiteXplore: 36228412

DOI: 10.1016/j.ejmech.2022.114814

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