The ubiquitin-proteasome system is one of the main pathways for cellular protein degradation. In recent years, methods for artificially degrading target proteins through UPS have been developed. Targeted protein degradation agents are highly useful as tools for discovery research, and they are also being developed as new therapeutic approaches. Several targeted protein degraders are currently being used in clinical trials. However, almost all targeted protein degradation technologies have been developed for cytoplasmic proteins. The G protein-coupled receptor (GPCR) superfamily represents one of the most important drug targets, but examples of GPCR degradation are limited.
Recently, researchers from Monash University published an article titled “The application of targeted protein degradation technologies to G protein-coupled receptors” in the British Journal of Pharmacology. The researchers reviewed previous cases and provided insights into different strategies that have been employed to apply targeted protein degradation to GPCRs. They also discussed whether alternative approaches used for degrading other integral membrane proteins could be applicable to GPCR degradation.
GPCRs are transmembrane proteins consisting of seven domains that can be activated by various stimuli, including light, neurotransmitters, peptides, and hormones. Upon activation, GPCRs undergo conformational changes and interact with heterotrimeric G proteins. The heterotrimeric G proteins then stimulate the production of second messengers, ultimately leading to changes in cellular processes such as transcription, metabolism, and migration. Therefore, GPCRs are involved in almost every physiological process. In fact, approximately 30% of the drugs on the market currently act through GPCRs, with more than half of them antagonizing GPCR signaling.
One of the major mechanisms for regulating individual protein levels within cells is the ubiquitin-proteasome system. Understanding UPS has led to the development of targeted protein degradation (TPD) technologies. Compared to traditional inhibitors, proteolysis-targeting chimeras (PROTACs) have several advantages. Firstly, because they induce degradation instead of inhibition, all functions of the targeted protein are halted until the protein is resynthesized. Therefore, the therapeutic effect typically lasts longer. Secondly, PROTACs have catalytic activity, with a degradation molecule being recycled to degrade multiple molecules of the protein of interest (POI). This means that lower doses can be used to achieve the same effect. This theoretically allows for tissue specificity in degrading the POI, thereby avoiding off-target effects.
In summary, although the number of reports on novel TPD methods is rapidly increasing, most degraders target cytoplasmic proteins, with only a few targeting multi-transmembrane proteins. Only a limited number of studies have explored GPCR-specific degradation using PROTACs or PROTABs. Whether a particular approach will be more successful for GPCR degradation remains to be observed. Nevertheless, this paves the way for the discovery of future GPCR degraders.