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.