Quick Project Snapshot
Enabling technologies for structure based drug design at G protein coupled receptors
G protein-coupled receptors (GPCRs) are a large family of proteins (>800 gene members) located on the surface of all cells in the body, particularly in the brain. They sense stimuli such as light, smells, hormones and neurotransmitters, and initiate cellular responses to these cues. GPCR signalling controls virtually every physiological process in the body, making these receptors the targets of many current drugs treating conditions like pain, hypertension, schizophrenia and asthma. 13 out of the top 50 prescription drugs sold in the USA in 2010 were GPCR targeting drugs, making these the largest class of drug targets; in fact, they accounted for more than $US28 billions of sales that year in the USA alone. While this seems impressive, up to 80% of this receptor family remain untargeted by drugs, even though many are strongly associated with disease. This reflects the difficulty associated with identifying and optimizing drugs that act at GPCRs.
Most GPCRs are activated though the interaction, or binding, of natural ligands such as hormones or neurotransmitters (e.g. adrenaline, dopamine, oxytocin) to the GPCR’s ligand binding site (Figure 1). A major challenge in GPCR drug discovery is achieving receptor selectivity. The GPCR gene super-family is made up of numerous sub-families that are activated by the same ligand, but may control different physiological processes. This means that the binding or “docking” site (Figure 1) of the ligand is very similar in these family members. Typically in drug discovery we search for synthetic compounds that can also bind to this receptor site, to change the signalling of the receptor, independent to its natural ligand. One of the main reasons for drug side effects however, is that these drugs may also bind to similar sites on other receptor family members (off targets), causing physiological response that are unwanted. Thus we need new ways to identify and design more selective GPCR targeting drugs to treat many diseases.
Structure-based drug design
To achieve receptor selectivity, we need to understand how natural ligands, and drug candidates, bind to receptors at the atomic level (Figure 1). This then allows the design of new drugs with optimized interactions for a specific receptor, making the drug more selective. This process is called structure-based drug design.
GPCR stabilization to facilitate structure-based drug design
To probe the atomic-level structures of GPCRs, we need to be able to purify these receptors from cells. A huge challenge has been that most GPCRs are very unstable and “fall apart” during purification, or during the experiments needed to perform “structure-based drug design”. We work on developing new technologies to get around this problem, such as Cellular High-throughput Encapsulation Solubilization and Screening, or CHESS, which allows us to engineer very stable receptors for drug discovery. The CHESS technology was spun out into a biotechnology company called G7 Therapeutics in 2013. Stabilised GPCRs can be produced in cells such as bacteria, purified and stored in the freezer until needed. This technology has some limitations however, and we are constantly working on developing new methods to further our understanding of the structure of many different GPCRs with the ultimate goal of designing better drugs.
Receptor Structure and Drug Discovery Laboratory
Protein instability poses a major barrier to the characterisation and deployment of many proteins into industrial and biotechnological applications. Membrane proteins are a class of proteins that are particularly unstable, yet are highly important as they are the main targets for most prescription drugs. Membrane proteins are located on the surface of all types of cells and are involved in processes such as sensing neurotransmitters, driving neural impulses and responding to drug treatment. The instability of membrane proteins, however, makes them difficult to study. We use novel technology (CHESS) to engineer stabilised membrane proteins, particularly neuropeptide-binding G protein-coupled receptors (GPCRs), to aid in elucidating the atomic level mechanisms that govern their function and to facilitate novel drug discovery.
A particular focus of the laboratory is engineering members of the relaxin receptor family to enable greater understanding of how these receptors work at the molecular level and in turn enable the design of drugs targeting these important receptors. We also use this technology to engineer highly stable versions of other protein classes, such as fluorescent proteins and enzymes, for biotechnological and industrial applications.
All Projects by this LabEnabling technologies for structure based drug design at G protein coupled receptorsDesigning allosteric modulators of the neurotensin receptor 1 (NTS1) as potential drugs for schizophreniaDrug discovery targeting α1-adrenoceptors (α1-ARs)
The Neuropeptides Division primarily conducts multi-disciplinary studies on the relaxin family of peptides/hormones and their receptors. The division focuses on determining the role of these peptides and the receptors they target a wide range of physiological and disease states. These studies are coupled with fundamental drug discovery research on both these and other peptides and their G protein-coupled receptors. The aim of this research is to develop new biological knowledge and fundamental understanding about how to best therapeutically target these peptide systems with the long term view to develop drugs which target the peptide receptors to treat vascular, fibrotic, metabolic and psychiatric diseases.
An example of the success of this approach is the completion of a Phase III trial using the hormone relaxin for the treatment of acute heart failure by the Swiss Pharmaceutical Company Novartis. A Phase IIIb trial is ongoing and the relaxin drug, serelaxin, has been approved in Russia to treat patients with acute heart failure. Hence fundamental research on the mechanism of action of a hormone, in the case of relaxin pioneered at the Florey by the former Neuropeptides Division Head, Prof Geoffrey Tregear, can ultimately lead to its use to treat disease in patients.