Biodiversity2Drugs—Renaissance of exploring nature-derived peptides for GPCR ligand discovery

GPCR drug discovery from nature—G protein-coupled receptors (GPCRs) are a cornerstone of therapeutic innovation, representing the largest and most versatile family of drug targets in the human body (Lorente et al., 2025). These receptors play a crucial role in regulating nearly all physiological processes, making them essential targets for addressing a wide range of conditions, from metabolic disorders to cancer. Nature-derived small molecules and peptides have been fundamental for the development of many successful GPCR therapeutics (Muratspahić et al., 2019). Morphine, originally derived from the poppy plant Papaver somniferum, was one of the first GPCR ligands to be found in nature and continues to play a vital role in managing both chronic and acute pain. For example, angiotensin-converting enzyme inhibitors in clinical use to treat hypertension were originally derived from peptides found in snake venom. Exendin-4 is a venom peptide found in the saliva of the lizard Heloderma suspectum, which was the first incretin-based drug to be approved, owing to its improved stability over endogenous GLP-1. It paved the way for the development of next-generation GLP-1 receptor agonists such as semaglutide, now widely used for the treatment of type 2 diabetes and obesity. These transformations of biomolecules into life-saving drugs underscore the potential of natural peptides as blueprints for the next generation of GPCR-targeted drug discovery efforts.