Natural product-based screening led to the discovery of a novel PXR agonist with anti-cholestasis activity

作者：Huang, Dong; Zhao, Ying-yuan; Wang, Rui-min; Li, Wei; Yuan, Fang-yu; Yan, Xue-long; Yang, Xiao; Tang, Gui-hua; Yin, Sheng^*; Bi, Hui-chang^*

来源：Acta Pharmacologica Sinica, 2022, 43(8): 2139-2146.

DOI：10.1038/s41401-021-00793-3

• cholestasis
• pregnane X receptor
• PXR agonist
• Euphorbiaceae
• lathyrane diterpenoid
• anti-cholestasis drugs

Cholestasis is a major cause of a series of bile flow malfunction-related liver diseases. Pregnane X receptor (PXR) is a key regulator in endo- and xeno-biotics metabolism, which has been considered as a promising therapeutic target for cholestasis. In this study we conducted human PXR (hPXR) agonistic screening using dual-luciferase reporter gene assays, which led to discovering a series of potent hPXR agonists from a small Euphorbiaceae diterpenoid library, containing 35 structurally diverse diterpenoids with eight different skeleton types. The most active compound 6, a lathyrane diterpenoid (5/11/3 ring system), dose-dependently activated hPXR with a high selectivity, and significantly upregulated the expression of hPXR downstream genes CYP3A4 and UGT1A1. In LCA-induced cholestasis mouse model, administration of compound 6 (50 mg.kg(-) (1). d(-1), ip) for 7 days significantly suppressed liver necrosis and decreased serum levels of AST, ALT, Tbili, ALP, and TBA, ameliorating LCA-induced cholestatic liver injury. We further revealed that compound 6 exerted its anti-cholestatic efficacy via activation of PXR pathway, accelerating the detoxification of toxic BAs and promoting liver regeneration. These results suggest that lathyrane diterpenoids may serve as a promising scaffold for future development of anti-cholestasis drugs.

• 单位
  南方医科大学; 中山大学