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A novel long-acting oxyntomodulin analogue eliminates diabetes and obesity in mice

Tao Ma1, Su Huo1, Bing Xu1

  • 1School of Chinese Materia Medica, Beijing University of Chinese Medicine, Liangxiang Campus, Fangshan District, Beijing, 102488, PR China.

European Journal of Medicinal Chemistry
|July 19, 2020
PubMed

Insights

Novel oxyntomodulin (OXM) analogues show potential for treating obesity and diabetes. A modified, PEGylated OXM analogue demonstrated significant weight loss and improved metabolic health in mouse models.

Area of Science:

  • Metabolic research
  • Peptide therapeutics
  • Obesity and diabetes research

Background:

  • Oxyntomodulin (OXM) acts as a dual agonist for glucagon (GCG) receptor (GCGR) and glucagon-like peptide 1 (GLP-1) receptor (GLP-1R).
  • Native OXM exhibits weak in vitro activation of GCGR and GLP-1R, limiting its therapeutic efficacy.
  • Structural modifications and chimeric peptide design yielded novel OXM analogues with improved receptor activation.

Purpose of the Study:

  • To develop novel oxyntomodulin analogues with enhanced and balanced GCGR/GLP-1R activation.
  • To evaluate the pharmacological effects of a PEGylated OXM analogue in preclinical models of obesity and diabetes.
  • To assess the potential of the analogue as an anti-diabetic and anti-obesity therapeutic candidate.

Main Methods:

  • Chimeric peptide sequence design to create novel OXM analogues.
  • Chemical conjugation with polyethylene glycol (PEG) for sustained release.
  • Pharmacological evaluation in db/db and diet-induced obese (DIO) mouse models.

Main Results:

  • The PEGylated OXM analogue demonstrated dose-dependent hypoglycemic effects and significant body weight loss.
  • Chronic administration normalized adiposity, improved lipid metabolism, and reduced liver steatosis.
  • Enhanced insulin stimulation and improved insulin resistance were observed.

Conclusions:

  • The developed PEGylated OXM analogue shows significant potential as a novel anti-diabetic and anti-obesity therapeutic.
  • The analogue may also be a candidate for treating nonalcoholic steatohepatitis (NASH) due to its effects on insulin sensitivity.
  • Further exploration of this modified OXM analogue is warranted for clinical development.
Keywords:
Dual agonistsGlucagon receptorGlucagon-like peptide 1 receptorObesityOxyntomodulin analoguesType 2 diabetes mellitus

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