Selection and progression of unimolecular agonists at the GIP, GLP-1, and glucagon receptors as drug candidates

Peptides. 2020 Mar;125:170225. doi: 10.1016/j.peptides.2019.170225. Epub 2019 Nov 28.


The continued global growth in the prevalence of obesity coupled with the limited number of efficacious and safe treatment options elevates the importance of innovative pharmaceutical approaches. Combinatorial strategies that harness the metabolic benefits of multiple hormonal mechanisms have emerged at the preclinical and more recently clinical stages of drug development. A priority has been anti-obesity unimolecular peptides that function as balanced, high potency poly-agonists at two or all the cellular receptors for the endocrine hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon. This report reviews recent progress in this area, with emphasis on what the initial clinical results demonstrate and what remains to be addressed.

Keywords: GIP; GLP-1; Glucagon; Obesity; Poly-agonism; Type 2 diabetes.

Publication types

  • Review

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Drug Design
  • Gastric Inhibitory Polypeptide / agonists*
  • Glucagon / chemistry
  • Glucagon / metabolism*
  • Humans
  • Obesity / drug therapy*
  • Obesity / metabolism
  • Obesity / pathology
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology*
  • Receptors, Gastrointestinal Hormone / agonists*
  • Receptors, Glucagon / agonists*
  • Structure-Activity Relationship


  • Peptide Fragments
  • Receptors, Gastrointestinal Hormone
  • Receptors, Glucagon
  • Gastric Inhibitory Polypeptide
  • Glucagon
  • gastric inhibitory polypeptide receptor