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Updated: Aug 24, 2026
Monitoring GPCR-β-arrestin1/2 Interactions in Real Time Living Systems to Accelerate Drug Discovery
Published on: June 28, 2019
Use of the BRET 7TM receptor/beta-arrestin assay in drug discovery and screening
1Department of Molecular Screening, 7TM Pharma, Fremtidsvej 3, 2970 Hørsholm, Denmark. AHED@7tm.com
Abstract:
To perform functional cell-based screening assays on seven-transmembrane (7TM) receptors, also known as G-protein coupled receptors, at least three distinct assays are currently needed to screen for G(alphas), G(alphai/0) or G(alphaq/11) signaling receptors. Therefore, there has long been a desire for a universal screening assay that could be used to screen all 7TM receptors independent of their signaling pathway. The receptor/beta-arrestin interaction is common to virtually all 7TM receptors. Therefore, an assay based on this interaction should achieve just that. Bioluminescence resonance energy transfer technology can be used to measure the receptor/beta-arrestin interaction in living cells but due to various technical and biological reasons, the use of the technology for compound screening has been limited. The recent development of beta-arrestin mutants that significantly improve the assay signal, in combination with new improved instrumentation, has transformed bioluminescence resonance energy transfer technology from being a highly specialized research tool in molecular pharmacology to a more drug screening-friendly technique that is useful in an industrial setting.
Insights
A new universal assay for seven-transmembrane (7TM) receptors, also known as G-protein coupled receptors, has been developed. This assay utilizes bioluminescence resonance energy transfer technology to screen all 7TM receptors, regardless of their signaling pathway.
Area of Science:
- Pharmacology
- Molecular Biology
- Biotechnology
Background:
- Screening seven-transmembrane (7TM) receptors, also known as G-protein coupled receptors, typically requires multiple assays for different signaling pathways (Gαs, Gαi/o, Gαq/11).
- A universal assay for all 7TM receptors, independent of their specific signaling pathway, has been a long-standing goal in drug discovery.
- The interaction between 7TM receptors and β-arrestin is a conserved mechanism across nearly all 7TM receptors.
Purpose of the Study:
- To develop a universal screening assay for seven-transmembrane (7TM) receptors that is independent of their signaling pathway.
- To leverage the conserved receptor/β-arrestin interaction for a unified screening approach.
- To adapt bioluminescence resonance energy transfer (BRET) technology for efficient and broad 7TM receptor screening.
Main Methods:
- Utilizing bioluminescence resonance energy transfer (BRET) technology to measure receptor/β-arrestin interactions in living cells.
- Employing newly developed β-arrestin mutants to enhance assay signal quality.
- Integrating improved instrumentation to facilitate high-throughput compound screening.
Main Results:
- The developed assay successfully measures the receptor/β-arrestin interaction, a common pathway for 7TM receptors.
- Advancements in β-arrestin mutants and instrumentation have overcome previous limitations of BRET technology for screening.
- BRET technology has been transformed into a more accessible and drug screening-friendly technique.
Conclusions:
- A universal assay based on receptor/β-arrestin interaction using BRET technology is feasible for screening all 7TM receptors.
- Recent technological improvements have made BRET a viable and powerful tool for industrial drug screening.
- This universal assay approach simplifies the screening process for G-protein coupled receptors, enhancing efficiency in drug discovery.
