The cell signaling switchboard just got a little bigger and a little more intricate: five orphan receptors and 17 candidate peptide ligands have been found to connect with each other. Also, nine receptors with recognized ligands have been found to connect with six previously published and 16 potential new peptide ligands. Overall, the known peptidergic system has been expanded from 348 to 407 interactions, an increase of 17%.

This expansion is significant because the peptidergic system, the cell signaling network that encompasses the G protein-coupled receptors (GPCRs) and the molecules that activate them, is targeted by about one-third of all approved drugs. Historically, the discovery of GPCR-ligand signaling systems has often translated into clinical opportunities. The newfound GPCR-ligand signaling systems, then, may stimulate research into their physiological roles and therapeutic potential.

This point was emphasized by David E. Gloriam, professor of drug design and pharmacology at the University of Copenhagen. Gloriam and his colleagues, along with collaborators from the University of North Carolina at Chapel Hill and Thomas Jefferson University, introduced the new signaling systems in a paper (“Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors”) that appeared October 31 in the journal Cell.

“Researchers can spend their whole career studying one GPCR signaling system because their therapeutic potential is vast, as shown by the sheer number of medical drugs targeting them,” said Gloriam. “We have identified five new such systems. This doesn’t happen every day, and it might have huge implications for drug development.”

The human cell has a wide variety of receptors on its surface to which many molecules and therapeutic drugs can bind, activating signal mechanisms inside the cell that help regulate different physiological functions. GPCRs are the largest (and a very important) family of receptors on human cells.

One-third of all approved drugs target GPCRs in one way or the other. However, for about one-third of GPCRs, the scientific community does not know which molecules, or ligands, bind to the receptor and activate a signal.

In the current study, the researchers evaluated peptides that function as signaling molecules because they represent around 71% of all known ligands that bind to GPCRs and because they are increasingly tested in clinical trials. In short, peptides were a good place to start in the search for new signaling molecules.

“Using three orthogonal biochemical assays,” the authors of the Cell article wrote, “we pair 17 proposed endogenous ligands with five orphan GPCRs [BB3, GPR1, GPR15, GPR55, and GPR68] that are associated with diseases, including genetic, neoplastic, nervous, and reproductive system disorders. We also identify additional peptides for nine receptors with recognized ligands and pathophysiological roles.”


Graphical abstract from the Cell article showing how new cell signaling systems were identified.

The potential peptide ligands were identified from all the proteins in a cell, the so-called proteome, consisting of around 20,000 proteins. The researchers focused on those that are secreted from the cell, as peptides that work as signaling molecules need to be secreted. They then filtered out all those with a previously known function.

In the research project, they then used machine learning to predict what potential peptides could be ligands for GPCRs. The calculations took into account genomes from more than 300 species and attempted to answer to what extent the peptides were “evolutionary conserved” or had the same characteristics as peptides in the species.

“In combining computational drug design with pharmacology, machine learning, and genomics, we have used a truly collaborative method in order to identify these new aspects of human biology. We would not have been able to identify this many pairs had it not been for the interdisciplinary nature of our method,” noted Gloriam.

The researchers selected 218 potential ligands which they screened against 21 receptors with three complementary orthogonal assays. The first assay evaluated physical mass distribution inside the cell; the second assay, internalization of the receptor in the cell; and the third assay, the recruitment of a protein called β-arrestin. All three techniques were used because using only one might have caused the researchers to miss some signals that use other pathways.

The researchers assert that their approach is of demonstrated predictive power and is applicable not only to peptide-GPCR systems, but also to many other peptide-protein systems. The current findings, however, already suggest potentially fruitful avenues of study. Specifically, the newly identified signaling systems have high translational potential as therapeutic targets.

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