Affiliation:
1. 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
2. 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
Abstract
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-O-(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, 10b, which selectively antagonizes FXR over other nuclear receptors. Compound 10b can differentially modulate the downstream genes of FXR, including with the upregulation of the CYP7A1 gene. In vivo testing revealed that 10b (100 mg·Kg−1) 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 10b 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 10b represents a promising candidate for the treatment of nonalcoholic steatohepatitis (NASH).
Funder
NSFC
CAMS Innovation Fund for Medical Sciences
National Key New Drug Creation and Manufacturing Program
Subject
Drug Discovery,Pharmaceutical Science,Molecular Medicine
Reference39 articles.
1. The first completed genome sequence from a teleost fish (Fugu rubripes) adds significant diversity to the nuclear receptor superfamily;Maglich;Nucleic Acids Res.,2003
2. The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer;Sun;Nat. Rev. Gastroenterol. Hepatol.,2021
3. Farnesoid X receptor (FXR): Structures and ligands;Jiang;Comput. Struct. Biotechnol. J.,2021
4. Mori, H., Svegliati Baroni, G., Marzioni, M., Di Nicola, F., Santori, P., Maroni, L., Abenavoli, L., and Scarpellini, E. (2022). Farnesoid X Receptor, Bile Acid Metabolism, and Gut Microbiota. Metabolites, 12.
5. Chenodeoxycholic Acid: An Update on Its Therapeutic Applications;Fiorucci;Handb. Exp. Pharmacol.,2019
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