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. 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. increase in urinary volume with no loss of electrolytes. conserved structural motif of cyclotides comprising a head-to-tail cyclic backbone and a cystine-knot in which an embedded ring formed by two disulfide bonds is threaded by a third disulfide bond. specific characteristics of a given molecule such as size, shape, or solubility shared with other molecules, which are considered as precursors of drugs (lead compounds). measure of ligand potency; it defines the ligand concentration that produces 50% of the maximum effect (Emax) or reduces the response/binding by 50%, respectively. peptide that resembles sequence or structure of enkephalin, a neuropeptide that binds to opioid receptors. insertion of a bioactive peptide epitope into a naturally occurring stable peptide scaffold, thereby generating a more stable peptide while retaining biological activity. persistent elevation of peripheral blood eosinophilic leukocytes greater than 1.5 × 109 l−1. measure of ligand affinity; it is the equilibrium dissociation constant that indicates the concentration at which 50% of the receptor binding sites are occupied by the ligand. domain of Kunitz-type protease inhibitors consisting of about 60 amino acid residues stabilized by three disulfide bonds. ligand-dependent selectivity for activating a certain signaling pathway of a receptor relative to a reference (e.g., the endogenous peptide ligand). genetic disorder associated with occurrence of numerous cysts within the kidneys as well as other organs. biologically active small chemicals produced by microbes or plants, which are not directly required for normal growth, development, and reproduction. They are often involved in interspecies communication or defense. variety of amino acid sequences within peptides or proteins likely evolved due to natural selection. the ability of biomolecules such as peptides or proteins to tolerate amino acid substitutions, insertions, or deletions within the backbone chain that do not change the overall fold. referred to as T2Rs or TAS2Rs, belong to a family of ∼25 human GPCRs that enable perception of bitter taste, or more generally are activated by ‘bitter’ substances, not only in the tongue. agents which induce tone and contractions of the uterus muscle. mixture of toxic substances produced by an animal for prey capture and defense.