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Biased Agonism of GPR84 as a Novel Dual Anti-inflammatory and Pro-repair Mechanism

Project description

Biased agonist of GPR84 as a novel anti-inflammatory drug

Dysregulation of the innate immune system might result in chronic inflammation, which is linked to multiple degenerative diseases. GPR84 is a member of the immunometabolic G protein-coupled receptor family and is involved in the inflammatory response. Biased agonism (the ability of a receptor to differentially activate downstream signalling pathways) is well-known for G protein-coupled receptor signalling. Scientists of the EU-funded GPR84 project recently discovered a biased agonist of GPR84 which stimulates pro-repair response phagocytosis in macrophages without the induction of pro-inflammatory chemotaxis. The aim of the project is to develop this promising but metabolically unstable small molecule into a viable lead candidate and carry out key proof-of-concept experiments on animal models of inflammation.

Objective

Elevated local and systemic inflammation has been shown to play a central role in multiple diseases. An important cellular mechanism leading to chronic increased inflammation is dysregulation of the innate immune system. A drug that modulates macrophage function, suppressing the pro-inflammatory response while maintaining pro-repair function would represent a major breakthrough in the treatment of multiple degenerative diseases.
Our host group very recently identified a biased agonist of an immunometabolic receptor, GPR84, which failed to induce chemotaxis (pro-inflammatory response) while stimulating phagocytosis (pro-repair response) in both murine and human macrophage (ACS Chem. Biol. 2019). This is an important discovery of a small molecule along with a defined molecular target and cellular mechanism which, for the first time, is capable of blocking a pro-inflammatory response while stimulating a pre-repair response in both mouse and human macrophage.
These results are extremely exciting and demonstrate the translational potential of our approach, but the small molecule they identified, while a useful in vitro tool which we have shared with the scientific community, cannot be progressed to in vivo proof-of-concept experiments because it is too metabolically unstable. We are therefore applying to the MSCA IF to seek medicinal chemistry support to drive a hit-to-lead project to evolve our small molecule hit into a lead candidate with appropriate properties for progression in vivo to carry out key proof-of-concept experiments in animal models of inflammation. This in vivo efficacy data will be pivotal to underpin a future funding application to support drug discovery and development campaigns.

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Coordinator

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Net EU contribution
€ 224 933,76
Address
Wellington square university offices
OX1 2JD Oxford
United Kingdom

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Region
South East (England) Berkshire, Buckinghamshire and Oxfordshire Oxfordshire
Activity type
Higher or Secondary Education Establishments
Links
Other funding
€ 0,00