Professor Arthur Christopoulos is the Professor of Analytical Pharmacology and Dean of the Faculty of Pharmacy and Pharmaceutical Sciences at Monash University. He is a world leader in drug discovery of G protein coupled receptors (GPCRs), particularly through multidisciplinary studies of allosteric modulation and biased agonism as novel biological paradigms to treat a broad range of diseases. Professor Christopoulos is the recipient of the NHMRC Peter Doherty Investigator Grant Award (Leadership) for his research into allosteric modulation of muscarinic receptors for the treatment of neurocognitive deficits.
My main passion has always been molecular pharmacology. In particular, drug discovery for neuropsychiatric disorders, especially cognitive deficits associated with diseases like schizophrenia and Alzheimer's disease.
When I was 16, I knew that A) I wanted to be a pharmacist and B) that I wanted to cure schizophrenia. I achieved ‘A’. I am still working on ‘B’, but the passion for discovery science and its translational potential, especially neuropsychiatry, has remained consistent throughout my career.
The ‘question’, rather than any given technique, has always been the driving force for my research. Careers are always punctuated by one or more ‘A-ha!’ moments and some can lead to nothing, but others can lead to breakthroughs. Dating back to my PhD, I discovered a biological paradigm on a super family of cell surface proteins that lends itself to many other diseases outside of neuropsychiatry.
G protein-coupled receptors (GPCRs) are the largest group of cell surface proteins. GPCRs are the main conduits by which humans can sense our extracellular environment, and we convert their signals inside our cells to maintain homeostasis.
Most medicines act on GPCRs by targeting the protein’s natural ‘on-off’ switch, which is either done via the body’s natural hormones or chemically by exogenous substances and drugs. What I discovered was the equivalent of the protein’s ‘dimmer-switch’ that modulates that actions of the traditional ‘on-off’ switch. This dimmer switch mechanism means that the activity of GPCRs can be dialed up or down to predetermined levels which, straight away, changed the way we can discover whole new classes of drugs because we can be more selective towards any given disease; in essence, we can ‘dial the drug to the disease’.
Suddenly, we can discover medicines that are both selective for the GPCR and the disease and are also very sensitive to ‘tissue context’, i.e., the difference in the targeted cellular environment between health and disease. This mechanism results in a higher potential for ‘built in’ safety, higher degrees of efficacy than traditional medicines, and has thus opened a whole new area of drug discovery.
But how do you prove a ‘universal’ biological paradigm while trying to also have a ‘targeted’ career? I was fortunate that when I came back to Australia to start my lab after completing my PhD that I managed to do both. Working with my colleague and good friend, Professor Patrick Sexton, and subsequently with Professor Roger Summers, the 3 of us pooled our resources and complementary skills set and ended up with a large and multidisciplinary lab that was, essentially, half the size of a department. This was not a common model of collaboration, retention of individual recognition, nor vehicle for mentoring at that time.
Australia is now known as a powerhouse with GPCR pharmacology and research, as well as drug discovery and structure biology, but it took us over 20 years to build it collaboratively.
Throughout my career I’ve learnt to always be generous with my time and ideas. The power of collaboration and the value of treating everyone, at any career stage, the same, is also critical to truly successful research.
With my students and postdocs, I always try and remove silos, because when you take the traditional constraints off the table, the sky is the limit. It’s also a great reminder for them to always be prepared for surprises and to not be too precious with their own research. I am particularly thrilled that my former postdoc and mentee, Associate Professor Alisa Glukhova, received the NHMRC Peter Doherty Investigator Grant Award (Emerging Leadership) the same time as I received my award.
There are always going to be more troughs than peaks in health and medical research, and it’s the peaks that are going to have to keep you going through those troughs. That is the nature of fundamental discovery science, because there are so many exciting avenues that it will lead to; some sooner, some later. I always retain a translational focus too, knowing that discovery science is the engine that feeds the translation.
My goal with the research generated by this Investigator Grant is to develop a new class of ‘dimmer switch’ medicines for clinically treating cognitive disorders moving forward.
Receiving the 2025 NHMRC Peter Doherty Investigator Grant Award for Leadership is a testament to the nature of the research team and the collaboration that has excelled us to this point. This recognition confirms that Australia is world leading in discovery science and how we are innovatively approaching major global health burdens.