A GLP-1 Peptide Discovered in Bullfrogs Outperformed Semaglutide for Blood Sugar and Weight Control | Research

The takeaway

Researchers discovered a GLP-1 analogue from bullfrogs and optimized it into a compound (2f) that showed superior effects on food intake, blood sugar control, and body weight compared to semaglutide in animal models.

Superior to semaglutide
The optimized bullfrog GLP-1 analogue 2f showed better effects on food intake, glycemic control, and body weight than semaglutide in preclinical animal models.

What the researchers found

Bullfrog GLP-1 (bGLP-1) showed the highest potency among natural GLP-1 analogues screened from fish and amphibians. Through structure-activity optimization and long-acting modifications, the researchers created analogue 2f, which showed superior effects on food intake, glycemic control, and body weight compared to semaglutide.

Using the bGLP-1 sequence as a scaffold, they also designed dual GLP-1/glucagon receptor agonist (3o) and triple GLP-1/GIP/glucagon receptor agonist (4b), both of which demonstrated significant therapeutic effects on lipid regulation, glycemic control, and body weight in preclinical testing.

Why it matters

Nature remains a powerful source for drug discovery. Finding a GLP-1 analogue from bullfrogs that outperforms semaglutide highlights the potential of natural peptides as starting points for next-generation obesity and diabetes drugs. The ability to use this natural scaffold for designing multi-receptor agonists further demonstrates the versatility of this approach.

How the study worked

Researchers screened GLP-1 analogues from fish and amphibians for receptor potency, then selected bullfrog GLP-1 for optimization. They conducted structure-activity relationship studies, made long-acting modifications, and tested candidates in animal models for effects on food intake, blood glucose, and body weight. They also used the bullfrog GLP-1 sequence to engineer dual and triple receptor agonists targeting GLP-1, glucagon, and GIP receptors, evaluating their effects on metabolism and body weight.

What this study cannot tell us

All testing was conducted in animal models, and preclinical superiority over semaglutide does not guarantee the same advantage in humans. Pharmacokinetics, safety, and long-term effects have not been established. The study does not report on potential immunogenicity of a frog-derived peptide in human applications. Clinical development would require extensive further testing.

How to read the evidence

This is a preclinical drug discovery study with animal model testing. While the results are promising and the methodology rigorous for this stage, no human data exist. The comparison to semaglutide is preclinical only.

When this study was published

Published in 2024, this study represents current efforts to discover next-generation GLP-1-based therapeutics from natural sources.

The bigger picture

The GLP-1 receptor agonist market is dominated by semaglutide and tirzepatide, but the search for more potent and versatile alternatives continues. This study demonstrates that natural peptide diversity — from sources as unexpected as bullfrogs — can yield leads that surpass current drugs in preclinical testing. The dual and triple agonist designs from the same scaffold represent the cutting edge of metabolic drug development.

Questions still open

Will the bullfrog-derived GLP-1 analogue maintain its superiority over semaglutide in human clinical trials?
Could the triple agonist 4b offer advantages over tirzepatide for obesity and diabetes treatment?
Are there additional natural GLP-1 variants from other species that could yield even more potent drug candidates?

Common questions

How was a diabetes drug discovered from a bullfrog?

GLP-1 is a hormone found across many species, with natural variations in its sequence. Researchers screened GLP-1 peptides from fish and amphibians and found that the bullfrog's version was the most potent at activating the GLP-1 receptor. They then optimized it further using medicinal chemistry techniques to create a long-acting drug candidate.

Could this bullfrog-derived peptide replace semaglutide?

In animal studies, the optimized version (compound 2f) outperformed semaglutide for reducing food intake, blood sugar, and body weight. However, animal results don't always translate to humans, and extensive clinical trials would be needed before it could become an approved treatment. The researchers also used it to design more advanced dual and triple agonists.

Read the original research

Discovery of a Novel Glucagon-like Peptide-1 (GLP-1) Analogue from Bullfrog and Investigation of Its Potential for Designing GLP-1-Based Multiagonists.

Journal of medicinal chemistry, 67(1), 180-198

View on PubMed ↗Publisher’s paper ↗

Citation

Jiang, Neng; Su, Di; Chen, De; Huang, Shutong; Tang, Chunli; Jing, Lin; Yang, Caiyan; Zhou, Zhongbo; Yan, Zhiming; Han, Jing. (2024). Discovery of a Novel Glucagon-like Peptide-1 (GLP-1) Analogue from Bullfrog and Investigation of Its Potential for Designing GLP-1-Based Multiagonists.. Journal of medicinal chemistry, 67(1), 180-198. https://doi.org/10.1021/acs.jmedchem.3c01049