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Targeting peptide G-protein coupled receptors (GPCRs) for novel drug development

Modern GPCR drug development is encumbered by a lack of information about the molecular structure underlying GPCR function and the reliance on cell-based assays that are prone to false positives in drug screening.

Aims

Projects are available on multiple GPCR targets with training in various techniques. 

The largest single class of drug targets is the G Protein-Coupled Receptor (GPCR) family, which were targets for 13 of the top 50 prescription drugs sold in the USA in 2010 (26%).

While the past 10 years have seen advances in our knowledge of GPCR structures peptide GPCRs, especially those with large structured ectodomains (ECDs), remain poorly understood. This is mainly because the flexibility of linkers joining the ECDs to the transmembrane domains (TMDs) impedes crystallization. Hence the study of complex peptide receptors requires different approaches. 


Our laboratory targets peptide GPCRs for drug development utilizing state-of-the-art molecular pharmacology, biochemical and nuclear magnetic resonance (NMR) techniques. These techniques enable us to map the native peptide binding sites of these receptors and determine the mechanisms of receptor activation as well their cell signalling characteristics.

A complete understanding of the mechanism of ligand binding and activation is required to design drugs targeting these receptors. Furthermore we are utilizing novel techniques to study the receptor structures (see project below) and are also studying ligand interactions with receptor domains using soluble receptor domains and NMR (A/Prof Gooley, Bio21).

These studies are complemented by peptide drug development projects and small molecule screening projects with collaborators. Additionally, we are working with pharmaceutical industry partners (e.g. Takeda and Novartis to facilitate drug development efforts). 


 

Recent Publications: 
1. Sethi A, Bruell S, Patil N, Hossain MA, Scott DJ, Petrie EJ, Bathgate RAD*, Gooley PR* (2016) The complex binding mode of the peptide hormone H2 relaxin to its receptor RXFP1. Nature Communications, 7: 11344 
2. Bruell S, Sethi A, Smith N, Scott DJ, Hossain MA, Wu Q-P, Guo Z-Y, Petrie EJ, Gooley PR, Bathgate RAD (2017) Distinct activation modes of the Relaxin Family Peptide Receptor 2 in response to insulin-like peptide 3 and relaxin. Scientific Reports 7: 3294 
3. Diepenhorst NA, Petrie EJ, Chen CZ, Wong A, Hossain MA, Bathgate RAD*, Gooley PR* (2015) Investigation of interactions at the extracellular loops of the relaxin family peptide receptor 1 (RXFP1). Journal of Biological Chemistry, 289: 34938-34952 
4. Kong RCK, Petrie EJ, Mohanty B, Ling J, Lee JCY, Gooley PR and Bathgate RAD (2013) RXFP1 utilises hydrophobic moieties on a signalling surface of the LDLa module to mediate receptor activation. Journal of Biological Chemistry 288: 28138-28151 
5. Bathgate RAD, Halls ML, Van der Westhuizen ET, Callander GE, Kocan M and Summers RJ (2012) Relaxin Family Peptides and Their Receptors. Physiological Reviews. 93: 405–480 

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