G protein-coupled receptors (GPCRs) are in the research spotlight in a recent Nature review by Hauser and colleagues (article). Recent breakthroughs in structural biology and innovations in biotechnology have brought GPCRs into the spotlight for two main reasons: 1) the ability to modulate GPCRs via allosteric sites, and 2) the use of biased agonism. This has brought on emerging GPCR research that puts them front and center in the frontier of what precision medicine has promised.
What are GPCRs?
GPCRs are one of the 5 protein families in our system and are involved in various processes in the body. As a receptor, they detect molecules outside the cell and activate internal signal transduction pathways and, ultimately, cellular responses. There is nothing new about these receptors being drug targets as they are participants and thus targets in a wide range of diseases from neurological problems to cancer to mental disorders. The fact that they are accessible on the cell surface (thus druggable) account for them being over 1/3 of the targets in medicinal drugs. (Read Hauser et al., 2018 in Cell) It is that fact, that makes their potential in drug discovery so exciting right now, as they not only hold potential for new drugs but also vast improvements on old drugs.
What breakthroughs in structural biology?
One of the most frustrating aspects of these receptors is that they are constantly shifting between different structural formations at different triggers and different times. As such, drugs targeting GPCRs have generally been developed without the help of high-resolution structural information, until now. With the help of recent innovations in biotech, we can now not only capture the crystal structures of receptors and ligand-receptor complexes – providing vast opportunity for structure-based drug discovery and design, but also many more receptors have become accessible – leading to new opportunities for both novel and established GPCR targets.
What is the promise of precision medicine and how do GPCRs fit in?
The limitations of medicine are not specific; they are in fact the overly broad strokes of treatment, the vagueness of our understanding. Drug development today now looks at those processes through the lens of refining those broad strokes into not only fine lines but perhaps even one day individualized treatment.
In this new era of freeze-frame and video assistant referees, it is only right that researchers now have got the tools to precisely start understanding the rules navigating these biological processes by capturing the different structures of GPCRs. Defining their distinct characteristics changes not only the game but also the field; drug delivery will be able to take into account the multiple cellular environmental factors that we need, to find their precise pathway. The use of allosteric sites to modulate GPCRs is essentially being able to alter the receptor through an alternative site on the membrane, for example an ion channel. This produces a wide range of possibilities for new approaches in drug development, such as spatial and temporal selectivity – essentially attempting to transform what has traditionally been an on/off switch to a dimmer with a timer (and in turn more precision). Likewise, the use of biased agonism adds in this concept of multidimensional GPCR signaling; building upon the previous example, it would be similar to using multiple sources of different types of lights (pixie lights or small flashlights rather than one overarching fixture) to achieve the precise effect desired. This level of precision in drug development would aim to reduce a significant portion of the unwanted side effects of drugs.
The new promise of research is precision medicine – whether it is in genetics or GPCRs – its potential is in the horizon, though in most cases still out of reach. The innovations in biotech have opened up new avenues for researchers in these fields to not only navigate the influence of bias, allostery and kinetics on disease states, but also they can be just more accurately characterized and we will have pieces to puzzles that have been out of focus for a long time.
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