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

Abstract

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.

Keywords: animal venom; drug discovery; ligand design; natural product; peptide; plant.

Figure 1

(A) Plants constitute the best source of nature-derived GPCR ligands. (B) Taste 2, aminergic, as well as opioid and cannabinoid GPCRs are leading targets of natural products. (C) Trend in discovery of small molecules (524) versus peptides (104) as nature-derived GPCR ligands from 1980 to 2018. Ligands before 1980 were not included.

Figure 2

Classical and Emerging Approaches of Peptide Drug Discovery to Identify Novel G Protein- Coupled Receptor (GPCR) Ligands. Classical approaches used for the isolation and characterization of nature-derived peptides from various sources include three major steps: (A) isolation and purification methods (e.g., solid-phase extraction and chromatography), and (B) structure elucidation by mass spectrometry (MS), nuclear magnetic resonance (NMR) spectroscopy, and X-ray crystallography. Emerging discovery strategies of peptides will focus on (A′) genome- and transcriptome-mining, and mass spectrometry-based peptidomics, (B′) structure-based design utilizing GPCR structures and computational methods, as well as (B′) improved peptide synthesis using chemistry methods and recombinant production. Both the classical and emerging approaches will be followed by pharmacological assays by ligand binding and functional screening (high-throughput if applicable).