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

The largest single class of drug targets is the G Protein-Coupled Receptor (GPCR) family, which were targets for ~30% of prescription drugs sold in the USA in 2010. However current drugs only target a small proportion of the GPCR family and peptide GPCRs, although showing great potential as targets for treating many diseases, are poorly targeted with drugs. 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.

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 protein engineering techniques that enable these normally highly unstable proteins to be produced and purified for structural studies using advanced protein NMR techniques, crystallography and Cryo-EM (also see projects from A/Prof Daniel Scott). Our studies are complemented by peptide drug development projects and small molecule screening projects with collaborators. Additionally, we are working with pharmaceutical industry partners (eg. Takeda and Novartis) to facilitate drug development efforts. Honours, Masters and PhD projects are available on multiple GPCR targets with training in various techniques as outlined above.

Relevant Publications:

Ashish Sethi, Shoni Bruell, Tim Ryan, Fei Yan, Mohammad Hossein Tanipour, Yee-Foong Mok, Chris Draper-Joyce, Yogesh Khandokar, Riley D. Metcalfe, Michael D. W. Griffin, Daniel J. Scott, Mohammad Akhter Hossain, Emma J. Petrie, Ross A. D. Bathgate*, Paul R. Gooley* (2021) Structural insights into the unique modes of relaxin-binding and tethered-agonist mediated activation of RXFP1 and RXFP2.  Journal of Molecular Biology. 433: Article 167217

Bumbak F, Thomas T, Noonan-Williams BJ, Vaid T, Yan F, Whitehead AR, Bruell, S, Kocan, M, Tan X, Johnson MA, Bathgate RAD, Chalmers DK, Scott DJ & Gooley PR (2020). Conformational changes in tyrosine 11 of neurotensin are required to activate the neurotensin receptor 1. ACS Pharmacology & Translational Science. 3:4, 690-705

Wu F-J, Williams LM, Abdul-Ridha A, Gunatilaka A, Vaid T, Kocan M, Whitehead A, Griffin MDW, Bathgate RAD, Scott DJ & Gooley PR (2020). Probing the correlation between ligand efficacy and conformational diversity at the α1A-adrenergic receptor. Journal of Biological Chemistry 295:7404-7417

Hoare BL, Bruell S, Lew MJ, Hossain MA, Inoue A, Scott DJ, Bathgate RAD (2019) Multi-component mechanism of H2 relaxin binding to RXFP1 through NanoBRET. iScience 11: 93–113

Wong LLL, Scott DJ, Kaas Q, Hossain MA, Rosengren KJ, Bathgate RAD (2018) Distinct but overlapping binding sites of agonist and antagonist at the Relaxin Family peptide 3 (RXFP3) receptor. Journal of Biological Chemistry 293: 15777-15789