GPCRomics: An Approach to Discover GPCR Drug Targets

Abstract

G protein-coupled receptors (GPCRs) are targets for ~35% of approved drugs but only ~15% of the ~800 human GPCRs are currently such targets. GPCRomics, the use of unbiased, hypothesisgenerating methods (e.g., RNA-sequencing [RNA-seq]), with tissues and cell types to identify and quantify GPCR expression, has led to the discovery of previously unrecognized GPCRs that contribute to functional responses and pathophysiology and that may be therapeutic targets. The combination of GPCR expression data with validation studies (e.g., signaling and functional activities) provides opportunities for the discovery of disease-relevant GPCR targets and therapeutics. Here, we review insights from GPCRomic approaches, gaps in knowledge and future directions by which GPCRomics can advance GPCR biology and the discovery of new GPCRtargeted drugs.

Transcriptomic analysis of pulmonary artery smooth muscle cells identifies new potential therapeutic targets for idiopathic pulmonary arterial hypertension

“…Further studies are needed to define the relationship between GPCR expression and the activation of G s /G i /G 12/13 ‐coupled GPCRs. DE of GPCRs can identify receptors that may contribute to pathophysiology and may be potential therapeutic targets, but such receptors must be assessed functionally, perhaps even if their expression is unchanged or decreased in PASMCs from PAH patients (Insel et al, 2019). For example, our analysis reveals that PAR1 ( F2R ) is very highly expressed in PASMCs.…”

The Olfactory Receptor Family 2, Subfamily T, Member 6 (OR2T6) Is Involved in Breast Cancer Progression via Initiating Epithelial-Mesenchymal Transition and MAPK/ERK Pathway

“…In clinical trials, 23 GPCR-targeted drugs are being developed for cancer treatment (36). However, the majority of human GPCRs were not targets for drugs because of our limited knowledge of their signaling mechanisms (37). In the present study, our findings in OR2T6 may help to broaden the molecular mechanism of GPCRs-induced breast cancer and to develop new therapeutic strategies for breast cancer patients in the future.…”

G protein-coupled receptors: structure- and function-based drug discovery

“…The shift of peptide C-terminus ( a ) and ECD ( b ) is indicated as red arrows. The peptides urocortin 1 (UCN1) 1 bound to CRF1R (light blue, PDB code: 6PB0), UCN1 2 bound to CRF2R (salmon, PDB code: 6PB1), PACAP38 (red, PDB code: 6P9Y), long-acting PTH (LA-PTH, green, PDB code: 6NBF), GLP-1 (cyan, PDB code: 5VAI), sCT (yellow, PDB code: 6NIY), and CGRP (magenta, PDB code: 6PB1) are shown as cartoons. Binding poses of the antagonist (green) and allosteric ligand (salmon) are shown as sticks ( c , PDB codes: 4K5Y, 5EE7, 4Z9G, 5VEW, and 5VEX).…”

“…Located on the cell membrane, they transduce extracellular signals into key physiological effects. 1 Their endogenous ligands include odors, hormones, neurotransmitters, chemokines, etc., varying from photons, amines, carbohydrates, lipids, peptides to proteins. GPCRs have been implicated in a large number of diseases, such as type 2 diabetes mellitus (T2DM), obesity, depression, cancer, Alzheimer’s disease, and many others.…”