Award details

Molecular and patho-physiological analysis of the G protein-coupled receptor GPR84

Reference	BB/T000562/1
Principal Investigator / Supervisor	Professor Graeme Milligan
Co-Investigators / Co-Supervisors	Professor Andrew Tobin
Institution	University of Glasgow
Department	College of Medical, Veterinary, Life Sci
Funding type	Research
Value (£)	901,395
Status	Current
Type	Research Grant
Start date	01/01/2020
End date	31/12/2023
Duration	48 months

Abstract

GPR84 is a poorly characterised G protein-coupled receptor. Although it is appreciated that high concentrations of medium chain fatty acids can activate GPR84, officially it remains an 'orphan' receptor as it remains uncertain if these are the true endogenous agonists. Despite being poorly studied a number of reports have suggested that activation or blockade of GPR84 might find therapeutic utility in conditions ranging from atherosclerosis to fibrosis and ulcerative colitis. In very recent times a number of more potent activators of GPR84 have been identified, many of which we have synthesised and assessed, and very recently we have screened for and identified the first series of high affinity competitive antagonists of the receptor. We will use these reagents, in concert with both our previously generated, and ongoing improvements of, receptor homology models, alongside direct structural studies, to define the molecular basis of recognition of each of orthosteric and allosteric agonists and antagonists of GPR84. Certain GPR84 agonists display bias in signalling and we will assess how this correlates with receptor phosphorylation and if a phosphorylation 'barcode' can be identified for agonists that act at distinct binding sites. We will also explore outcomes of activating or blocking GPR84 in immune cell populations in which this receptor is either expressed basally or in which pro-inflammatory signals are known to produce marked upregulation of the receptor. To link these studies directly to disease-related processes and to provide potential validation of GPR84 as a therapeutic target we will generate and characterise both GPR84 knock-out mice and a transgenic mouse line in which, as we have done previously for the related receptor free fatty acid receptor 2, we will replace mouse GPR84 with the human orthologue. We will use these animals to explore effects of regulating the activity of GPR84 in models of gut inflammatory diseases and fibrosis.

Summary

G protein-coupled receptors are trans-plasma membrane proteins that allow the transfer of information encoded by hormones and neurotransmitters into cells and tissues of the body and, by so doing, act to control physiological responses. They are both the largest group of such signal transducers and have proved to be the most useful in acting as the molecular targets for new medicines. Despite this, many GPCRs have not yet been targeted in this way because we currently know too little about their specific roles in the body and the potential usefulness or consequences of promoting or blocking their actions. The receptor GPR84 is a good example of this. It is known to be expressed by a range of key immune cell subtypes and also that its levels can be increased dramatically in such cells in many situations associated with inflammation. Moreover, it is known that levels of GPR84 on immune cells in the blood can be a useful indicator of the likely effectiveness of treatment of the lower gut inflammatory condition ulcerative colitis. There are also suggestions that either stimulating or blocking GPR84 might be useful approaches to treat conditions ranging from neuropathic pain to atherosclerosis. However, to date none of these suggestions have really been addressed in a substantive way. In very large part this reflects that until very recently no tool compounds have been available to block the action of GPR84 and, although it is known than certain fatty acids can activate GPR84 it requires very high concentrations that are probably not present normally in the circulating blood to do so. This suggests that activation of GPR84 may be produced by ligands other than fatty acids and it is also known that a molecule we generate in the body after eating broccoli and related vegetables is able to activate GPR84. We plan a comprehensive approach to understand the biological functions of this receptor that will employ each of novel chemical ligands that we have identified and characterised, and each of computational, structural and molecular biology-based studies designed to understand how such ligands activate or block the receptor. These will inform how such information can be used to develop ligands that are even more effective. We will also develop and use mice which either lack expression of GPR84 or in which we will replace the mouse version of GPR84 with the equivalent human receptor. Following initial characterisation we will use these mouse lines to study the capacity of activators and blockers of GPR84 to prevent or modify features of disease phenotypes. These studies will determine the likely potential to translate the outcomes from this programme of work to predict whether regulation of the activity of GPR84 may be useful in efforts to develop novel treatments for diseases in humans.

Impact Summary

Following a period in which G protein-coupled receptors (GPCRs) became less well represented in the therapeutic target portfolios of a number of major pharmaceutical companies recent years have seen a marked renaissance of interest. This reflects a number of features. Firstly, the rate of approval of new medicines that target GPCRs has been maintained over time, with many of these medicines acting via GPCRs that had not previously been exploited. Secondly, the emergence to prominence of a number of mid-size bio-pharmaceutical companies that focus almost exclusively on GPCRs as targets and which have taken advantage of the rapid increase in structural information on members of the GPCR superfamily to allow the application of structure-based drug design. Moreover, new modalities of ligand regulation of GPCRs have emerged that allow for more nuanced regulation of the functions of this protein family beyond simply 'on' and 'off'. Despite this effort, and a number of translational successes, many GPCRs remain 'hard to target'. Even when genetic and/or biomarker information suggests the potential of such 'hard to target' GPCRs, much underpinning work is required by the academic community to build up confidence and provide clear support for companies to invest heavily in programmes that target such receptors. Herein we will build on a substantial body of preliminary data we have generated on the 'orphan' receptor GPR84. At the current time a first-in-man clinical trial of a blocker of GPR84 for the treatment of ulcerative colitis failed to demonstrate efficacy whilst a set of very encouraging trials are ongoing to assess efficacy in a lung fibrotic condition of a molecule that has only low affinity as a blocker of GPR84. Current literature suggests potentially useful outcomes of regulating GPR84 in a range of inflammatory conditions and also in diseases that span neuropathic pain to atherosclerosis, as well as the fibrotic conditions detailed above. We believe that the results we generate in this project will have impact with the pharmaceutical industry. The initial beneficiaries in this regard will be our Industrial Partner Sosei Heptares. Outcomes will be shared with Sosei Heptares throughout the project, and ahead of public disclosure, giving the company a clear competitive advantage to ascertain directions for future internal, translational efforts. We have developed novel series of GPR84 antagonists that act competitively with orthosteric agonist ligands. Given that Galapagos NV and Prometic Life Sciences have either ongoing or completed clinical trials with ligands that have affinity at GPR84 it is certain both these companies will also have particular interest in the outcomes. The molecule trialled by Prometic has very low affinity at GPR84 and also potential polypharmacology as it is also able to active GPR40. The ligand trialled by Galapagos NV is a non-competitive antagonist of GPR84 as we have detailed in a recent joint publication with Galapagos. In preparatory work for this application we screened some 350,000 drug-like small molecules. We obtained a significant number of hits that display competitive antagonism of GPR84, one series of which we describe in the application. We have already received expressions of interest from large EU-based pharmaceutical companies based simply on this set of outcomes. We are thus aware of substantial pharmaceutical company interest in our studies and we anticipate this will develop further as we start to generate and publish data and outcomes from the programme we define. Companies are likely to benefit directly from our work as it will provide potential validation for a 'hard to target' GPCR for which substantial interest in already apparent. This may be to look more closely at areas of potential therapeutic interest or may also be directed specifically at the compound series we have identified.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	Immunology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	Industrial Partnership Award (IPA)

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