Selection and progression of unimolecular agonists at the GIP, GLP-1, and glucagon receptors as drug candidates
Abstract
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.
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Differences in in vitro cAMP potencies between human receptors and those of different pre-clinical models, particularly GIPR, can complicate translation of pre-clinical results to a clinical setting.
“However, differences in in vitro cAMP potencies between human receptors and those of different pre-clinical models, particularly with regard to GIPR, can complicate translation of pre-clinical results to a clinical setting [44].”
From Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice (2022) · cites this paper as [44]
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- Authors
- Knerr, P. J., Mowery, S. A., Finan, B., Perez-Tilve, D., Tschöp, M. H., & DiMarchi, R. D.
- Affiliations
- Helmholtz Munich (DE)
- Indiana University Bloomington (US)
- Corresponding author
- DiMarchi, Richard D.
- Venue
- Peptides
- Publisher
- Elsevier BV
- Published
- 2020-03
- Volume
- 125
- Pages
- 170225
- ISSN
- 0196-9781 (ISSN-L)
- OpenAlex
- W2989619493
- Cited by
- 49
- References
- 122
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 11 · 2021: 13 · 2020: 6
- FWCI
- 1.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Peptides (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Site cant be reached (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- GLP-1 receptor, glucose-dependent insulinotropic polypeptide receptor, glucagon receptor, obesity treatment, GIP/GLP-1 receptor agonist, peptide agonists
- MeSH terms
- Animals, Diabetes Mellitus, Type 2, Gastric Inhibitory Polypeptide, Glucagon, Humans, Obesity, Peptide Fragments, Receptors, Gastrointestinal Hormone, Structure-Activity Relationship, Drug Design, Receptors, Glucagon
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