Department of Chemistry


Date of this Version



ACS Chem Biol. 2021 February 19; 16(2): 251–263. doi:10.1021/acschembio.0c00950


ACS Chem Biol. Author manuscript; available in PMC 2021 September 29


Intercellular signaling events mediated by neuropeptides and peptide hormones represent important targets for both basic science and drug discovery. For many bioactive peptides, the protein receptors that transmit information across the receiving cell membrane are not known, severely limiting these signaling pathways as potential therapeutic targets. Identifying the receptor(s) for a given peptide of interest is complicated by several factors. Most notably, cell-cell signaling peptides are generated through dynamic biosynthetic pathways, can act on many different families of receptor proteins, and can participate in complex ligand-receptor interactions that extend beyond a simple one-to-one archetype. Here, we discuss recent methodological advances to identify signaling partners for bioactive peptides. Recent advancements have centered on methods to identify candidate receptors via transcript expression, methods to match peptide- peptidereceptor pairs through high throughput screening, and methods to capture direct ligand-receptor interactions using chemical probes. Future applications of the receptor identification approaches discussed here, as well as technical advancements to address their limitations, promises to lead to a greater understanding of how cells communicate to deliver complex physiologies. Importantly, such advancements will likely provide novel targets for treatment of a number of human diseases within the central nervous and endocrine systems.