The application of targeted protein degradation technologies to G protein‐coupled receptors

Abstract

The ubiquitin‐proteasome system is one of the major pathways for the degradation of cellular proteins. In recent years, methods have been developed to exploit the ubiquitin‐proteasome system to artificially degrade target proteins. Targeted protein degraders are extremely useful as biological tools for discovery research. They have also been developed as novel therapeutics with several targeted protein degraders currently in clinical trials. However, almost all targeted protein degrader technologies have been developed for cytosolic proteins. The G protein‐coupled receptor (GPCR) superfamily is one of the most important classes of drug targets, yet only limited examples of GPCR degradation exist. Here, we review these examples and provide a perspective on the different strategies that have been used to apply targeted protein degradation to GPCRs. We also discuss whether alternative approaches that have been used to degrade other integral membrane proteins could be applied to the degradation of GPCRs.

Highlights and hot topics in GPCR research from ‘Down Under’

“…Finally, three technology-based reviews highlight exciting new ways to discover and capitalise on drug targets. Keen et al (2024) explain how the promising technique of targeted protein degradation might be deployed for GPCRs. Clinical trials targeting cytosolic proteins are already underway using the proteolysis-targeting chimera (PROTAC) approach that involves the fusion of two molecules; one component binds to the protein target of interest, while the other acts as a 'warhead' to bring an E3 ubiquitin ligase into proximity to label the target protein for degradation.…”

PROTACs: Emerging Targeted Protein Degradation Approaches for Advanced Druggable Strategies

“…Since its creation, PROTAC technology has found widespread application in both the development of novel therapeutics and fundamental biological studies. Over time, the application of the PROTAC technology has benefited a variety of distinct protein categories, including nuclear receptors [ 13 ], kinases, G protein-coupled receptors (GPCRs) [ 14 ], trans-membrane proteins, small GTPases, epigenetic proteins [ 15 ], transcription factors, and protein aggregates [ 16 ]. A linker connecting an E3 ubiquitin ligase (E3)-recruiting ligand and a protein gives a PROTAC molecule its dual function [ 17 , 18 ].…”