By Dr Catriona Nguyen-Robertson MRSV

This article revisits Dr Christopher Draper-Joyce’s presentation to the Royal Society of Victoria in September 2021 as the recipient of the 2021 Phillip Law Postdoctoral Award.

The human body is composed of trillions of cells. Each individual cell communicates with others, and performs certain tasks within the collective to keep our bodies working. Their ability to send and receive signals is vital. When communication is disrupted, disease often follows.

Many therapeutic drugs used to treat a range of diseases target specific cell receptors – proteins on the cell surface that receive messages. Restore the communication, and you can restore normal function.

Using an interdisciplinary approach, Dr Christopher Draper-Joyce is exploring new approaches for developing safer and much improved options for therapeutics.

Cell communication (sans a mobile phone)

Numerous protein receptors in the body recognise a variety of signals to control cell behaviour. A message in the form of a signal molecule will bind to a receptor to elicit a response. The largest cell surface receptor family is G protein-coupled receptors (GPCRs). They are a large, diverse group of receptors that sit on cell membranes to respond to stimuli from outside the cell.

Humans have more than 1,000 different types of GPCRs, and each has a unique function. When they bind to their appropriate signal – neurotransmitters, hormones, metabolites, and even light photons – they trigger a cascade of molecular events within the cell, broadcasting the signal via effector proteins.

Importantly, because GPCRs are involved in so many cellular responses, they are excellent drug targets. These receptors regulate numerous diverse physiological processes and are easily accessed by drugs at the cell surface, making them of particular interest as pharmacological targets. In fact, GPCR targets comprise around 35% of all medicines currently approved by the USA’s Food and Drug Administration.^1,2

Targeting GPCRs as therapeutics

Traditional drug discovery approaches focus on the point that a signal molecule contacts the receptor, either aiming to block or enhance signalling. The challenge with this approach, however, is designing a drug that selectively only targets the particular GPCR you want, while avoiding similar-looking ones as all GPCRs have a similar structure. . For example, the places where dopamine, serotonin, acetylcholine, and adrenaline bind their respective receptors overlap in structure. If a drug is designed to block the location where one of these molecules binds, then there is a high chance it will block all of the different molecules from binding to their own GPCRs, resulting in unwanted side effects.

Another challenge in drug discovery is that receptor signalling is  often quite complicated. Because each GPCR triggers a cascade of signals in a cell when switched on, by manipulating one receptor, you are manipulating many signals at once. Using a drug to either completely switch or switch off a receptor could therefore result in negative impacts in addition to achieving the desired outcome. As an alternative approach, Christopher and other researchers design drugs that bind to the receptor in such a way that they modulate the signal rather than completely switching it on or off. Rather than designing a drug that fits snugly into the spot where the signal molecule usually binds its receptor, if the drug binds to a different part of the GPCR, it could act as a dimmer switch without completely disrupting signals.

Christopher’s team have recently unlocked the key that could lead to the development of alternative painkillers. With chronic pain affecting more than 3.2 million Australians and the costs of chronic pain expected to increase in the coming decades,³ there is an urgent need for new, non-opioid painkillers. The adenosine A1 receptor protein (a GPCR) has long been recognised as a promising therapeutic target, as it plays a role in sensing pain. However, because adenosine can bind to four different receptors to either enhance or inhibit pain, previous attempts to target it without off-target effects have failed.

Using a multidisciplinary approach with preclinical models and microscopy, Christopher and team produced a detailed visualisation of the A1 receptor protein structure. They achieved the first atomic-level snapshot of the pocket where drugs bind, and could therefore design a drug that enhances the ability of adenosine to bind the A1 receptor – without also binding to a region conserved across multiple GPCRs. His work also shows that it is possible to design drugs for specific diseases by better understanding the interplay between a signal molecule and its receptor, and exploiting their structural interactions.

While most traditional drugs are small molecules that somehow interfere with the binding of signal molecules to a receptor, Christopher is now also exploring the use of nanobodies in therapeutics. Antibodies are proteins that bind tightly and specifically to their target cells, and nanobodies are the versions found in camelid animals (camels, llamas, alpacas, etc.). The different structure of nanobodies allow them to bind to different parts of a receptor, while also being cheaper to produce and less sensitive to temperature fluctuations (which is a particularly important consideration for transport). Furthermore, the structure of nanobodies is such that they tend to have finger-like parts that can help them better reach into the grooves of their target receptors, which may aid researchers like Christopher to design drugs to modulate a receptor rather than completely switch it on or off. He is currently producing nanobodies that target various GCPRs in alpacas in the hope that they become viable therapies for cancer and other diseases.

Receptors, particularly GPCRs, are implicated in a plethora of diseases. Through a molecular understanding of how ligands and receptors interact, and how a drug can modulate the interaction, is greatly advancing drug discovery programs. These new protein visualisation technologies will pave the way for safer and more effective GPCR therapeutics.

Watch Dr Christopher Draper-Joyce’s presentation to the RSV in full at youtu.be/kDynzPYP5XU (or a 10-minute version at youtu.be/_6JmG-NcRU8).

References:

1. Hauser, A. S., et al. (2017). Trends in GPCR drug discovery: new agents, targets and indications. Nature Reviews. Drug Discovery, 16(12), 829–842. doi.org/10.1038/nrd.2017.178
2. Sriram, K., & Insel, P. A. (2018). G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs? Molecular Pharmacology, 93(4), 251–258. doi.org/10.1124/mol.117.111062
3. Painaustralia. (March 2019). The cost of pain in Australia. painaustralia.org.au/static/uploads/files/the-cost-of-pain-in-australia-final-report-12mar-wfxbrfyboams.pdf