Adhesion G protein-coupled receptors: opportunities for drug discovery

The seminal discovery of the novel activation mechanism of Adhesion GPCRs (aGPCRs)1,2, together with their strong and growing links to disease from human genetics and pre-clinical research, has prompted a rapid reconsideration of this unique family of receptors for classical drug discovery. However, while acknowledged as a sub-family of GPCRs by the IUPHAR3, these receptors are anything but classical with their complex gene structures, large multi-domain N-termini, autocatalytic cleavage and tethered ligands. Initially thought to have a purely structural role, the increasing functional complexity of this GPCR sub-family and the many, potentially unique mechanisms of modulation challenges the way we have perceived this protein class until now. Significantly, if 50% of non-sensory GPCRs are unexploited as drug targets4, this figure reaches 100% for aGPCRs so the potential to develop novel therapies could be substantial5. Here, we discuss the unique opportunities and challenges brought by aGPCRs in the context of drug discovery programs naturally starting with target identification then extending to target validation, assay building and safety considerations