Drug Design, Development and Therapy (May 2023)

Cinchonine, a Potential Oral Small-Molecule Glucagon-Like Peptide-1 Receptor Agonist, Lowers Blood Glucose and Ameliorates Non-Alcoholic Steatohepatitis

  • Xue H,
  • Xing HJ,
  • Wang B,
  • Fu C,
  • Zhang YS,
  • Qiao X,
  • Guo C,
  • Zhang XL,
  • Hu B,
  • Zhao X,
  • Deng LJ,
  • Zhu XC,
  • Zhang Y,
  • Liu YF

Journal volume & issue
Vol. Volume 17
pp. 1417 – 1432

Abstract

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Huan Xue,1,* Hao-Jie Xing,1,* Bin Wang,1 Chao Fu,1 Yu-Shan Zhang,1 Xi Qiao,1 Chao Guo,1 Xiao-Li Zhang,1 Bin Hu,1 Xin Zhao,1 Li-Jiao Deng,1 Xiao-Chan Zhu,1 Yi Zhang,1 Yun-Feng Liu2 1Department of Pharmacology, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China; 2Department of Endocrinology, First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi Zhang; Yun-Feng Liu, Tel +86-18835102847 ; +86-18703416169, Email [email protected]; [email protected]: The glucagon-like peptide-1 receptor (GLP-1R) is an effective therapeutic target for type 2 diabetes mellitus (T2DM) and non-alcoholic steatohepatitis (NASH). Research has focused on small-molecule GLP-1R agonists because of their ease of use in oral formulations and improved patient compliance. However, no small-molecule GLP-1R agonists are currently available in the market. We aimed to screen for a potential oral small-molecule GLP-1R agonist and evaluated its effect on blood glucose and NASH.Methods: The Connectivity map database was used to screen for candidate small-molecule compounds. Molecular docking was performed using SYBYL software. Rat pancreatic islets were incubated in different concentrations glucose solutions, with cinchonine or Exendin (9– 39) added to determine insulin secretion levels. C57BL/6 mice, GLP-1R−/− mice and hGLP-1R mice were used to conduct oral glucose tolerance test. In addition, we fed ob/ob mice with the GAN diet to induce the NASH model. Cinchonine (50 mg/kg or 100 mg/kg) was administered orally twice daily to the mice. Serum liver enzymes were measured using biochemical analysis. Liver tissues were examined using Hematoxylin-eosin staining, Oil Red O staining and Sirius Red staining.Results: Based on the small intestinal transcriptome of geniposide, a recognized small-molecule GLP-1R agonist, we identified that cinchonine exerted GLP-1R agonist-like effects. Cinchonine had a good binding affinity for GLP-1R. Cinchonine promoted glucose-dependent insulin secretion, which could be attenuated significantly by Exendin (9– 39), a specific GLP-1R antagonist. Moreover, cinchonine could reduce blood glucose in C57BL/6 and hGLP-1R mice, an effect that could be inhibited with GLP-1R knockout. In addition, cinchonine reduced body weight gain and food intake in ob/ob-GAN NASH mice dose-dependently. 100 mg/kg cinchonine significantly improved liver function by reducing the ALT, ALP and LDH levels. Importantly, 100 mg/kg cinchonine ameliorated hepatic steatosis and fibrosis in NASH mice.Conclusion: Cinchonine, a potential oral small-molecule GLP-1R agonist, could reduce blood glucose and ameliorate NASH, providing a strategy for developing small-molecule GLP-1R agonists.Graphical Abstract: Keywords: glucagon-like peptide-1 receptor, cinchonine, drug repurposing, non-alcoholic steatohepatitis, type 2 diabetes mellitus

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