Building the Next Generation of GPCR-Targeting Drugs

If you’re going to hunt for new drugs, targeting G-protein coupled receptors (GPCRs) would seem a good starting point. One third of marketed drugs hit this group of cell-membrane bound receptors, which are involved in almost every possible biological system. Activated by a wide range of ligands outside the cell that link onto the GPCR’s extracellular component, GPCRs mediate a variety of cellular responses via signal transduction pathways inside the cell, usually via activation of a G-protein. Many of the body’s hormones bind to GPCRs, and these receptors also reside in a host of different tissue types. Drugs targeting GPCRs therefore span most therapy areas, specialist or primary care, and may be small molecules, peptides, or large proteins. Just a few examples of GPCR-targeting drugs include household names such as loratadine (Claritin), fluoxetine (Prozac), and the triptans, including for instance sumatriptan (Imitrex/Imigran).

Yet there’s plenty of untapped potential, too. Scientists have identified more than 350 non-sensory GPCRs (the sensory ones, involved in taste, smell, and vision, are less useful in drug discovery as they bind exogenous ligands) and know the natural ligands for 233 of those, according to the Cambridge Healthtech Institute