How can we improve the measurement of receptor signaling bias?

Abstract

G protein-coupled receptors (GPCRs) are flexible and dynamic signaling entities that can adopt multiple active conformations upon activation [Citation1,Citation2]. However, each agonist stabilizes a distinct receptor conformation at a definite point of time allowing transmission of a specific conformational information to downstream transducers and effectors. This signaling modality known as biased agonism or functional selectivity has rapidly attracted interest as a means to improve drug discovery by screening for drug candidates that can direct their stimuli toward pathways that are therapeutically beneficial while avoiding those associated with adverse effects. Although appealing as a work plan, screening for biased ligands is a challenging process that needs to be correctly assessed and interpreted. In fact, numerous studies reported identifying compounds with biased signaling properties, but very few of those compounds have progressed to clinical testing, leaving open the question of whether it would be possible to translate a biased drug stimulus into a therapeutically desired response.