Professors Qiongming Xu and Yanli Liu reported a drug candidate for treating ulcerative colitis by targeting pyruvate carboxylase from anemoside B4 derivatives

Professors Qiongming Xu and Yanli Liu report a drug candidate for treating ulcerative colitis by targeting pyruvate carboxylase from anemoside B4 derivatives

Background:In 2019,our group reported that anemoside B4 (AB4) exhibits significant anti-inflammatory and immunomodulatory effects comparable to those of dexamethasone.Furthermore,AB4 showed notable efficacy in improving TNBS-induced colitis by inhibiting the NF-κB signaling pathway through the deactivation of S100A9. These original discoveries led us to obtaina national invention patent (ZL201910092465.7). Additionally, we have also published a series of research papers (Chinese Medicine, 2021, 16:11; Phytomedicine, 2019, 56, 136-146; Phytomedicine, 2019, 64, 152934, etc.).Recently, our research revealed that pyruvate carboxylase (PC) serves as the molecular target of AB4 in the treatment of IBD. Moreover, PC has been identified as a novel anti-inflammatory target (Inflammation Research, 2024, 73: 345-362). In this study, we aimed to enhance the anti-inflammatory activity and oral suitability of AB4 by preparing derivatives through structural modifications.

Highlight 1:Thein vivoandin vitroanti-inflammatory activity of A3-6 was significantly improved by the AB4 derivative.

Theapplication of AB4 is limited due to its high molecular weight and pronounced water solubility. To discover new effective agents for treating IBD, 28AB4 derivatives were synthesized, and their cytotoxic and anti-inflammatory activities were assessedin vitro. Among these derivatives, A3-6exhibited markedly superior anti-inflammatory activity compared to AB4.It significantly improved DSS-induced colitis symptoms in mice, with a notably lower oral effective dose than AB4.

Highlight 2:Pyruvate carboxylase plays a crucial role in regulating inflammation through metabolic reprogramming and has the potential to serve as an ideal target for colitis treatment.

Our research revealed that A3-6 bound to pyruvate carboxylase, leading to the inhibition of pyruvate carboxylase activity, the reprogramming of macrophage function, and the alleviation of colitis.

Significance:Our findings suggest that A3-6 is a promising therapeutic candidate for colitis and that pyruvate carboxylase is a new anti-inflammatory target for treating colitis.

Reference:

Lv LJ, Li QR, Wang KX, Zhao JP, DengKJ, Zhang R, Chen Z, Khan IA, Gui CS, Feng SX, YangSL, LiuYL*, XuQM*.Discovery of a new anti-inflammatory agent from anemoside B4 derivatives and its therapeutic effect on colitis by targeting pyruvate carboxylase.Journal of Medicinal Chemistry2024, Apr 30. Epub ahead of print.

Full-text link:doi: 10.1021/acs.jmedchem.4c00222.

Corresponding authors:

Yanli Liu is a professor at the College of Pharmaceutical Sciences, Soochow University. Since 2006, Dr. Liu has discovered a series of anti-inflammatory, antibacterial, and antitumor agents from several traditional Chinese medicines and has delved into their molecular mechanisms. She has published more than 50 academic papers as the corresponding author or first author inActa Pharmacol. Sin.,Phytother. Res.,J. Ethnopharmacol., and Chin. Med.,Phytomedicine,Phytochemistryand Brit J. Pharmacol.

Qiongming Xu is a professor at the College of Pharmaceutical Sciences, Soochow University. Dr. Xu has isolated and identified over 700 compounds from over 30 traditional Chinese medicines, including over 160 new compounds. He has published more than 80 academic papers as the corresponding author in J. Agric. Food Chem., Food Chem., J Med. Chem., J. Funct. Foods,Phytochemistry, Planta Med.,Acta Pharmacol. Sin.,Phytother. Res.,J. Ethnopharmacol., Chin. Med.,Phytomedicine, Cell Death Dis. and Brit J. Pharmacol., and obtained more than 30 national invention patents. In 2019, Dr. Xu's group discovered for the first time that anemoside B4 has significant anti-inflammatory and immunomodulatory effects through injection and identified pyruvate carboxylase as an anti-inflammatory target. His research has led to the approval of two new traditional Chinese veterinary medicines and one innovative traditional Chinese medicine under evaluation by the National Center for New Drug Evaluation.