DiscoveRx Corporation, GlaxoSmithKline (GSK) and Medical Research Council Technology (MRCT) have announced a three-way alliance to seek out natural substances that bind to G-protein-coupled receptors (GPCRs). Through the identification of the natural ligand for these receptors, it is anticipated that this work will identify and validate new drug targets that could ultimately help develop new therapies; compounds that modulate GPCRs are already the basis of many licensed medicines.

The human genome encodes roughly 350 GPCRs, which respond to substances known as ligands. These ligands include hormones, growth factors and proteins. Activation of the receptor by the ligand triggers signalling systems within the cell. These signalling systems are pivotal to normal cell biology and are involved in disease processes.

Despite intensive efforts, there remain at least 100 orphan GPCRs – receptors that have no known ligand or function. Identifying the ligand and role of these orphan GPCRs could potentially open up new areas of biology for therapeutic intervention and drug discovery.

This new industrial–academic collaboration will use the novel PathHunter™ ß-arrestin assay technology on an unprecedented scale to identify the ligands for some of these orphan GPCRs. This systematic approach will target the 100 ‘Family A’ GPCRs that remain classified as orphan receptors with no known biological ligand. After the identification of ligands, certain receptors will progress into high-throughput compound screens to be performed at either MRCT or GSK to identify lead molecules to support drug discovery.

GSK has had considerable success at pairing orphan GPCRs with ligands and will provide the GPCR ligand banks, laboratory equipment and laboratory space. DiscoveRx will provide access to stable cell lines expressing orphan GPCRs formatted in the PathHunter™ ß-arrestin assay (~90 orphan GPCRs), and MRCT will provide scientific staff to perform project activities and identify academic collaborators to characterize ligand-matched GPCRs.

G-protein-coupled receptors (GPCRs) are a family of proteins that are found widely throughout the body and play a fundamental part in physiology and pathophysiology. As such, they are potential targets for therapeutic intervention in many, if not most, diseases.