Nature-Derived Peptides: A Growing Niche for GPCR Ligand Discovery


Natural products have been and continue to be an important source of GPCRs ligands.

Over 600 natural GPCR ligands have been isolated from plants, animals, fungi, and bacteria; they predominantly target aminergic, opioid, cannabinoid, and taste 2 receptors.

At least 16 FDA-approved drugs targeting GPCRs are natural products, mainly small molecules from plants.

Nature-derived peptides isolated from bacteria, fungi, plants, and venomous animals, such as cone-snails, snakes, spiders, and scorpions are an emerging compound class for GPCR ligand discovery. They represent valuable starting points for GPCR drug development.

New technologies in peptide discovery and peptide chemistry allow for reliable identification of numerous nature-derived peptides and their synthesis to advance pharmacological screening, lead discovery and optimization, and eventually clinical applications.


G protein-coupled receptors (GPCRs) represent important drug targets, as they regulate pivotal physiological processes and they have proved to be readily druggable. Natural products have been and continue to be amongst the most valuable sources for drug discovery and development. Here, we surveyed small molecules and (poly-)peptides derived from plants, animals, fungi, and bacteria, which modulate GPCR signaling. Among naturally occurring compounds, peptides from plants, cone-snails, snakes, spiders, scorpions, fungi, and bacteria are of particular interest as lead compounds for the development of GPCR ligands, since they cover a chemical space, which differs from that of synthetic small molecules. Peptides, however, face challenges, some of which can be overcome by studying plant-derived compounds. We argue here that the opportunities outweigh the challenges.

Full text of the study can be accessed at the website of the publisher, or can be supplied on demand by email request to


Muratspahić E, Freissmuth M, Gruber CW. Nature-Derived Peptides: A Growing Niche for GPCR Ligand Discovery. Trends Pharmacol Sci. 2019 Apr 4. pii: S0165-6147(19)30046-X. doi: 10.1016/ Review. PubMed PMID: 30955896.

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