Receptor dimers and biased ligands: Novel strategies for targeting G protein-coupled receptors

Abstract

G protein-coupled receptors (GPCRs) are the largest superfamily of membrane receptors. They regulate physiological and pathological processes such as metabolic homeostasis, cell proliferation and differentiation, and the immune response, and are one of the most important classes of drug targets, being targeted by 30–40 % of marketed drugs. A growing number of studies continue to reveal the complexity of GPCRs, especially their ability to interact with each other to form higher-order structures such as homodimers and heterodimers, which have different functions than monomers, and are involved in disease development and progression. The existence of GPCR homodimers and heterodimers is opening up new directions in drug discovery and development to harness their therapeutic potential. Particularly striking is the ability of GPCR dimers to trigger unique biased signalling pathways, which exquisitely balance the relationship between therapeutic effects and side effects. By suppressing adverse reactions and enhancing beneficial drug effects, GPCR dimers provide an unprecedented opportunity to minimise side effects, maximise therapeutic efficacy and enhance safety. This review aims to highlight the latest research advances in GPCR dimerization and GPCR-biased signalling, focusing on the development of dimer-targeting and biased ligands as innovative drugs that will likely provide new strategies for treating GPCR-related diseases as well as a better understanding of drug design for compounds that target GPCRs. GPCRs will play an increasingly important role in precision medicine and personalised therapy, leading us towards a safer, more efficient and smarter pharmaceutical future.