Biased agonism: An emerging paradigm in GPCR drug discovery

Abstract

G protein coupled receptors have historically been one of the most druggable classes of cellular proteins. The members of this large receptor gene family couple to primary effectors, G proteins, that have built in mechanisms for regeneration and amplification of signaling with each engagement of receptor and ligand, a kinetic event in itself. In recent years GPCRs, have been found to interact with arrestin proteins to initiate signal propagation in the absence of G protein interactions. This pinnacle observation has changed a previously held notion of the linear spectrum of GPCR efficacy and uncovered a new paradigm in GPCR research and drug discovery that relies on multidimensionality of GPCR signaling. Ligands were found that selectively confer activity in one pathway over another, and this phenomenon has been referred to as ‘biased agonism’ or ‘functional selectivity’. While great strides in the understanding of this phenomenon have been made in recent years, two critical questions still dominate the field: How can we rationally design biased GPCR ligands, and ultimately, which physiological responses are due to G protein versus arrestin interactions? This review will discuss the current understanding of some of the key aspects of biased signaling that are related to these questions, including mechanistic insights in the nature of biased signaling and methods for measuring ligand bias, as well as relevant examples of drug discovery applications and medicinal chemistry strategies that highlight the challenges and opportunities in this rapidly evolving field.

Macrophage Migration Inhibitory Factor-CXCR4 Receptor Interactions

“…5) The results that MIF activates G protein signaling in mammalian cells expressing CXCR3/CXCR4 hybrid receptors or in S. cerevisiae cells expressing CXCR4 indicate that the cryptic site also induces a conformational change in transmembrane helix 6 to accommodate G protein interactions necessary for signaling (81). Our experiments do not detect any CXCR4-␤-arrestin 2 interactions induced by MIF indicating a possible biased G protein signaling, but this needs further investigation (82,83). 6) Finally, the MIF catalytic cavity is involved in MIF-CXCR4 interactions that can be targeted for therapeutic intervention without affecting the homeostatic function of CXCL12 and CXCR4.…”

Strategy for making safer opioids bolstered

“…In the past few years, it has become increasingly evident that different ligand molecules can activate receptors in different ways 10 . In the case of G-protein-coupled receptors (the family of receptors to which the µOR belongs), some ligands selectively activate a signalling pathway that involves the eponymous G protein, whereas others activate signalling through a protein called β-arrestin-2.…”

Oxidized cholesteryl esters and inflammation

“…This dichotomy between LPS- and OxCE-mediated TLR4 responses attests, in addition to the pattern-recognition character of TLR4, to the TLR4 biased agonism, or functional selectivity. This emerging concept in the field of G-protein-coupled receptors (GPCR), explaining the instances when different ligands of the same receptor preferentially activate one signaling pathway over another, integrates new discoveries showing multidimensionality of GPCR signaling rather than the linear spectrum of GPCR responses [41, 42]. More work is needed to understand mechanisms responsible for biased agonism in TLR4 signaling and its implications for the development of chronic inflammatory diseases.…”