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

Drug Des Devel Ther. 2023 May 11:17:1417-1432. doi: 10.2147/DDDT.S404055. eCollection 2023.

Abstract

Purpose: 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.

Keywords: cinchonine; drug repurposing; glucagon-like peptide-1 receptor; non-alcoholic steatohepatitis; type 2 diabetes mellitus.

MeSH terms

  • Animals
  • Blood Glucose
  • Diabetes Mellitus, Type 2*
  • Glucagon-Like Peptide-1 Receptor / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Molecular Docking Simulation
  • Non-alcoholic Fatty Liver Disease* / drug therapy
  • Rats
  • Receptors, Glucagon / agonists
  • Receptors, Glucagon / metabolism
  • Receptors, Glucagon / therapeutic use

Substances

  • Blood Glucose
  • Glucagon-Like Peptide-1 Receptor
  • cinchonine
  • Receptors, Glucagon

Grants and funding

This research was funded by the NSFC (No. 81973378 and 82073909), Basic Research Plan in Shanxi Province of China (No. 202103021223219 and 20210302124584), FSKSC, and 1331KSC.