Discovery of a New Anti-Inflammatory Agent from Anemoside B4 Derivatives and Its Therapeutic Effect on Colitis by Targeting Pyruvate Carboxylase

Abstract

Anemoside B4 (AB4), a triterpenoidal saponin from Pulsatilla chinensis, shows significant anti-inflammatory activity, and may be used for treating inflammatory bowel disease (IBD). Nevertheless, its application is limited due to its high molecular weight and pronounced water solubility. To discover new effective agents for treating IBD, we synthesized 28 AB4 derivatives and evaluated their cytotoxic and anti-inflammatory activities in vitro. Among them, A3−6 exhibited significantly superior anti-inflammatory activity compared to AB4. It showed a significant improvement in the symptoms of DSS-induced colitis in mice, with a notably lower oral effective dose compared to AB4. Furthermore, we discovered that A3−6 bound with pyruvate carboxylase (PC), then inhibited PC activity, reprogramming macrophage function, and alleviated colitis. These findings indicate that A3−6 is a promising therapeutic candidate for colitis, and PC may be a potential new target for treating colitis.

Synthesis and Evaluation of 1,3-Disubstituted Imidazolidine-2,4,5-triones as Inhibitors of Pyruvate Carboxylase

“…Recent studies have reported on two small molecule inhibitors, erianin , and ZY-444, that demonstrate an exceptional ability to inhibit cancer cell growth, metastasis, and proliferation. Two more recent studies have reported that the natural product anemoside B4 achieves anti-inflammatory activity in a colitis animal model. , These phenotypic studies all propose that the target of these small molecules is PC, but detailed biochemical validation of these compounds has been limited. Using an alternative target-based approach, our group has previously identified 3-aryl-2-hydroxypropenoic acids as CT domain inhibitors of S. aureus pyruvate carboxylase ( Sa PC) .…”