Utilization of Biased G Protein-Coupled Receptor Signaling towards Development of Safer and Personalized Therapeutics

Abstract

G protein-coupled receptors (GPCRs) are involved in a wide variety of physiological processes. Therefore, approximately 40% of currently prescribed drugs have targeted this receptor family. Discovery of β -arrestin mediated signaling and also separability of G protein and β -arrestin signaling pathways have switched the research focus in the GPCR field towards development of biased ligands, which provide engagement of the receptor with a certain effector, thus enriching a specific signaling pathway. In this review, we summarize possible factors that impact signaling profiles of GPCRs such as oligomerization, drug treatment, disease conditions, genetic background, etc. along with relevant molecules that can be used to modulate signaling properties of GPCRs such as allosteric or bitopic ligands, ions, aptamers and pepducins. Moreover, we also discuss the importance of inclusion of pharmacogenomics and molecular dynamics simulations to achieve a holistic understanding of the relation between genetic background and structure and function of GPCRs and GPCR-related proteins. Consequently, specific downstream signaling pathways can be enriched while those that bring unwanted side effects can be prevented on a patient-specific basis. This will improve studies that centered on development of safer and personalized therapeutics, thus alleviating the burden on economy and public health.

The Emerging Role of Rab5 in Membrane Receptor Trafficking and Signaling Pathways

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GPCRs: The most promiscuous druggable receptor of the mankind

“…In GPCR signaling, the ability of a molecule to selectively activate one pathway without affecting another pathway is called biased agonism. Biased signaling occurs at different signaling proteins, including G proteins, GRKs, β-arrestins, and even at levels of the allosteric binding site ( Ilter et al, 2019 ). Since GPCR activation-induced two distinct signal waves, G protein-dependent signaling followed by β-arrestin-dependent signaling opens a new promising therapeutic future in the world of GPCRs.…”

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