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

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

  • Eur J Med Chem. 2022 Dec 15;244:114814. doi: 10.1016/j.ejmech.2022.114814.
Junjun Long 1,  Tianhao Ying 1,  Lei Zhang 1,  Tao Yu 1,  Jinhui Wu 1,  Yasen Liu 1,  Xiaoli Li 1,  Guoliang You 1,  Leiming Zhang 2,  Yi Bi 3
Affiliations

Affiliations

  • 1 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, PR China.
  • 2 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, PR China. Electronic address: zhangleiming2009@126.com.
  • 3 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, PR China. Electronic address: beeyee_413@163.com.
PMID: 36228412 DOI: 10.1016/j.ejmech.2022.114814
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.

Keywords

Anti-inflammatory; Fusidic acid; STING inhibitor; Sepsis.

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