Ma Hao, Bao Yunyang, Niu Shuaishuai, Wang Shaorong, Li Yiming, He Hongwei, Zhang Na, Fang Weishuo
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines & Ministry of Health Key Laboratory of Biosynthesis of Natural Products, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 2A Nan Wei Road, Beijing 100050, China.
Key Laboratory of Biotechnology of Antibiotics, The National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Pharmaceuticals (Basel). 2023 May 17;16(5):758. doi: 10.3390/ph16050758.
The farnesoid X receptor (FXR) plays a crucial role in regulating the metabolism of bile acids, lipids, and sugars. Consequently, it is implicated in the treatment of various diseases, including cholestasis, diabetes, hyperlipidemia, and cancer. The advancement of novel FXR modulators holds immense importance, especially in managing metabolic disorders. In this study, a series of oleanolic acid (OA) derivatives bearing 12β--(γ-glutamyl) groups were designed and synthesized. Using a yeast one-hybrid assay, we established a preliminary structure-activity relationship (SAR) and identified the most potent compound, , which selectively antagonizes FXR over other nuclear receptors. Compound can differentially modulate the downstream genes of FXR, including with the upregulation of the CYP7A1 gene. In vivo testing revealed that (100 mg·Kg) not only effectively inhibits lipid accumulation in the liver but also prevents liver fibrosis in both BDL rats and HFD mice. Molecular modeling indicated that the branched substitution of extends into the H11-H12 region of FXR-LBD, possibly accounting for its CYP7A1 upregulation, which is different from a known OA 12β-alkonate. These findings suggest that 12-glutamyl OA derivative represents a promising candidate for the treatment of nonalcoholic steatohepatitis (NASH).
法尼醇X受体（FXR）在调节胆汁酸、脂质和糖类代谢中起关键作用。因此，它与包括胆汁淤积、糖尿病、高脂血症和癌症在内的各种疾病的治疗有关。新型FXR调节剂的研发具有极其重要的意义，尤其是在管理代谢紊乱方面。在本研究中，设计并合成了一系列带有12β -（γ-谷氨酰）基团的齐墩果酸（OA）衍生物。通过酵母单杂交试验，我们建立了初步的构效关系（SAR），并鉴定出最有效的化合物，该化合物对FXR的选择性拮抗作用优于其他核受体。化合物 可以差异性地调节FXR的下游基因，包括CYP7A1基因的上调。体内试验表明（100 mg·Kg）不仅能有效抑制BDL大鼠和HFD小鼠肝脏中的脂质积累，还能预防肝纤维化。分子模拟表明 的支链取代延伸到FXR-LBD的H11-H12区域，这可能是其CYP7A1上调的原因，这与已知的OA 12β-链烷酸酯不同。这些发现表明12-谷氨酰OA衍生物 是治疗非酒精性脂肪性肝炎（NASH）的有前途的候选药物。
