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

In this study, we aimed to discover novel GLP-1 analogues
from
natural sources. We investigated GLP-1 analogues from fish and amphibians,
and bullfrog GLP-1 (bGLP-1) showed the highest potency. Starting with
bGLP-1, we explored the structure–activity relationship and
performed optimization and long-acting modifications, resulting in
a potent analogue called 2f. Notably, 2f exhibited superior effects on food intake, glycemic control, and
body weight compared to semaglutide. Furthermore, we explored the
usefulness of bGLP-1 in designing GLP-1-based multiagonists. Using
the bGLP-1 sequence, we designed novel dual GLP-1/glucagon receptor
agonists and triple GLP-1/GIP/glucagon receptor agonists. The selected
dual GLP-1/glucagon receptor agonist 3o and triple GLP-1/GIP/glucagon
receptor agonist 4b exhibited significant therapeutic
effects on lipid regulation, glycemic control, and body weight. Overall,
our study highlights the potential of discovering potent GLP-1 receptor
agonists from natural sources. Additionally, utilizing natural GLP-1
analogues for designing multiagonists presents a practical approach
for developing antiobesity and antidiabetic agents.