Are GPCRs Still a Source of New Targets?

Abstract

G-protein-coupled receptors (GPCRs) still offer enormous scope for new therapeutic targets. Currently marketed agents are dominated by those with activity at aminergic receptors and yet they account for only ~10% of the family. Progress up until now with other subfamilies, notably orphans, Family A/peptide, Family A/lipid, Family B, Family C, and Family F, has been, at best, patchy. This may be attributable to the heterogeneous nature of GPCRs, their endogenous ligands, and consequently their binding sites. Our appreciation of receptor similarity has arguably been too simplistic, and screening collections have not necessarily been well suited to identifying leads in new areas. Despite the relative shortage of high-quality tool molecules in a number of cases, there is an emerging, and increasingly substantial, body of evidence associating many as yet "undrugged" receptors with a very wide range of diseases. Significant advances in our understanding of receptor pharmacology and technical advances in screening, protein X-ray crystallography, and ligand design methods are paving the way for new successes in the area. Exploitation of allosteric mechanisms; alternative signaling pathways such as G12/13, Gβγ, and β-arrestin; the discovery of "biased" ligands; and the emergence of GPCR-protein complexes as potential drug targets offer scope for new and much improved drugs.

Oligomerization of GPCRs involved in endocrine regulation

“…The pathogenic triggers at GPCRs vary from hormonal dysregulation, virus infections, mutations, or interactions with autoantibodies. Interestingly, it was recently reported that 365 human GPCRs are potential drug targets (Garland 2013).…”

A cAMP Biosensor-Based High-Throughput Screening Assay for Identification of Gs-Coupled GPCR Ligands and Phosphodiesterase Inhibitors

“…1A). 1,2 Since GPCRs comprise one of the largest gene families and ~26% of marketed drugs work by modulating GPCR activation, 3,4 quantification of intracellular cAMP levels remains an important methodology in molecular pharmacological studies of GPCRs. In recent years, biosensors that monitor intracellular cAMP levels have been developed, and the ongoing improvement of these assays provides several opportunities compared with previously employed assays, 5 including the possibility to continuously measure the intracellular cAMP levels in real time.…”

The Use of Antibodies in Small-Molecule Drug Discovery

“…This is an important insight as GPCRs are attractive targets for drug development because of their role in cell-signaling cascades. 85 However, comparatively little is known about the structural changes associated with agonist or antagonist binding, as of the GPCRs, only rhodopsin has been crystallized in the multiple conformations required to understand the complex structural processes associated with ligand binding. 84 Alongside acting as structural chaperones, the use of antibodies as crystallization aids has been extended to provide vital mechanistic understanding in addition to structural information.…”