Projects per year
Personal profile
Biography
A cellular revolution
In the last five years Professor Patrick Sexton and colleagues have begun unravelling the complexities of drug action that could revolutionise pharmaceutical drug design. Their profound new knowledge of the complex interactions occurring on the surface of the body's cells challenges traditional views of how medicines work, and could lead to treatments so precise they can be tailored to individual patients.
Working within the Monash Institute of Pharmaceutical Science, Patrick is uncovering the secrets of the largest family of cell surface receptors: G protein-coupled receptors (GPCRs). These receptors allow communication between what moves around the body to inside cells, and are the largest drug target family in the human genome.
The established approach to drug design was based on a belief that all pathways activated by a receptor would be affected equally by drugs, with investigations of drug action limited to a single signalling pathway.
However, Patrick's research has discovered there is far more going on at the cell surface. Receptor activity is far broader than previously understood. Most receptors are now known to activate multiple pathways. Further complicating the process, individual drugs acting at the same receptor cause different activity.
This understanding creates the potential to develop drugs that selectively activate beneficial pathways and don't activate signals that are less beneficial and lead to side-effects.
"Traditionally held views of why drugs work are changing," Patrick says. "It is only recently that we have begun to understand why some drugs work better for some diseases versus others.
"A very significant element of that comes back to the fact that we didn't really mechanistically understand what these drugs were doing. Yes, we could get drugs to market but we were not necessarily predicting therapeutic effects in the way that we potentially could, and we were not directing the drugs to particular therapeutic end points as well as we could.
"These things are very important in whether we can actually create better medicines - medicines that could potentially be personalised to a patient, that target unmet medical needs and reduce side-effects."
Patrick's research has uncovered a whole new field of pharmacology.
However, traditional methods of understanding these complex cellular interactions no longer offer sufficient insight, and Patrick's team have produced a new 'chemical toolbox' to use in their work.
"We don't have a lot of information that tells about the relative importance of one pathway versus another, and we really haven't had the tools required to probe that," Patrick says. "So one thing we are trying to do is create that chemical toolbox, identify spectrums of behaviour of molecules and then be able to take those and move them into a physiological context and test the combinations of pathways to use.
"This information is critically important to progressing this field, but it is information that is lacking. We are working hard on it. We are constantly making new discoveries."
The goal at the end of all this hard work is producing better treatments for a range of neuropsychiatric diseases - such as schizophrenia and Alzheimer's - and metabolic diseases, including type-2 diabetes.
Their knowledge of previously unused chemical pathways means researchers could also potentially rescue the function of severely damaged cells. By creating drugs that bind at different, newly discovered, parts of the receptor Patrick's team believe they can actually resume communications with cells previously thought unreachable and attack the core elements of disease in patients that have traditionally been deemed beyond treatment.
Expertise related to UN Sustainable Development Goals
In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This person’s work contributes towards the following SDG(s):
Research area keywords
- Allosteric Modulation
- Biased Agonism
- Bivalent Ligand
- Drug Discovery
- Functional Selectivity
- REC
- Pharmacology
- Structure Function of Receptors
- Family B G Protein-Coupled Receptors
Network
-
Development of approaches for inactive, antagonist bound GPCR structures determination
Wootten, D., Sexton, P., Belousoff, M., Johnson, R. & Han, S.
22/02/22 → 21/02/26
Project: Research
-
Impact of membrane composition on cholecystokinin receptor structure and function
Miller, L. J. & Sexton, P.
1/01/22 → 30/11/25
Project: Research
-
Cryo‐EM structure determination of G protein‐coupled receptors
Sexton, P., Wootten, D., Belousoff, M., Nar, H., Weichert, D., Ebenhoch, R., Ou, Q. & Lee, D.
21/09/21 → 21/09/25
Project: Research
-
Optimisation of GPCR expression, purification and structure determination
Sexton, P., Wootten, D., Belousoff, M., Tovey, J. C., Williams, P. & Apelbaum, A.
7/04/21 → 6/04/25
Project: Research
-
Development of approaches for orphan GPCR structure determination
Sexton, P., Wootten, D., Belousoff, M., Zhang, C., Russell, I. C. & Flocco, M.
7/04/21 → 6/04/25
Project: Research
-
AM833 is a novel agonist of calcitonin family G protein–coupled receptors: Pharmacological comparison with six selective and nonselective agonists
Fletcher, M. M., Keov, P., Truong, T. T., Mennen, G., Hick, C. A., Zhao, P., Furness, S. G. B., Kruse, T., Clausen, T. R., Wootten, D. & Sexton, P. M., 1 Jun 2021, In: Journal of Pharmacology and Experimental Therapeutics. 377, 3, p. 417-440 24 p.Research output: Contribution to journal › Article › Research › peer-review
Open Access11 Citations (Scopus) -
Cryo-EM structure of the dual incretin receptor agonist, peptide-19, in complex with the glucagon-like peptide-1 receptor
Johnson, R. M., Zhang, X., Piper, S. J., Nettleton, T. J., Vandekolk, T. H., Langmead, C. J., Danev, R., Sexton, P. M. & Wootten, D., 12 Nov 2021, In: Biochemical and Biophysical Research Communications. 578, p. 84-90 7 p.Research output: Contribution to journal › Article › Research › peer-review
1 Citation (Scopus) -
Development of Novel 4-Arylpyridin-2-one and 6-Arylpyrimidin-4-one Positive Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor
Jörg, M., Khajehali, E., van der Westhuizen, E. T., C. Choy, K. H., Shackleford, D. M., Tobin, A. B., Sexton, P. M., Valant, C., Capuano, B., Christopoulos, A. & Scammells, P. J., 8 Jan 2021, In: ChemMedChem. 16, 1, p. 216-233 18 p.Research output: Contribution to journal › Article › Research › peer-review
Open Access1 Citation (Scopus) -
Evolving cryo-EM structural approaches for GPCR drug discovery
Zhang, X., Johnson, R. M., Drulyte, I., Yu, L., Kotecha, A., Danev, R., Wootten, D., Sexton, P. M. & Belousoff, M. J., 2 Sep 2021, In: Structure. 29, 9, p. 963-974.e6 18 p.Research output: Contribution to journal › Article › Research › peer-review
Open Access5 Citations (Scopus) -
Exploring Ligand Binding to Calcitonin Gene-Related Peptide Receptors
Deganutti, G., Atanasio, S., Rujan, R. M., Sexton, P. M., Wootten, D. & Reynolds, C. A., 26 Aug 2021, In: Frontiers in Molecular Biosciences. 8, 14 p., 720561.Research output: Contribution to journal › Article › Research › peer-review
Open Access
Activities
- 1 Submissions to industry or govt committees, commissions and inquiries
-
Theme Leader
Patrick Sexton (Member)
10 Nov 2011Activity: External Academic Engagement › Submissions to industry or govt committees, commissions and inquiries