Attributes novel drug candidate: Constitutive GPCR signal bias mediated by purinergic receptors.

G protein-coupled receptors (GPCRs) can transmit signals via G protein-dependent or independent pathways due to the conformational changes of receptors and ligands, which is called biased signaling. This concept posits that ligands can selectively activate a specific signaling pathway after receptor activation, facilitating downstream signaling along a preferred pathway. Biased agonism enables the development of ligands that prioritize therapeutic signaling pathways while mitigating on-target undesired effects. As a class of GPCRs located on the surface of cell membranes, the discovery and clinical implementation of adenosine and P2Y receptors purinergic signaling modulators have progressed dramatically. However, many preclinical drug candidates targeting purinergic receptors have failed in clinical trials due to limited efficacy and/or severe on-target undesired effects. To overcome the key barriers typically encountered when transitioning ligands into the clinic, the renewed impetus has focused on the modulation of purinergic receptor function by exogenous agonists/antagonists and allosteric modulators to exploit biased agonism. This article provides a brief overview of the research progress on the mechanism of purinergic biased signal transduction from the conformational changes of purinergic GPCRs and biased ligands primarily, and highlights therapeutically relevant biased agonism at purinergic receptors.