GPR84 as a therapeutic target

GPCRs as targets

With 475 drugs targeting 108 unique GPCRs it is estimated that GPCRs are targets for ~35% of approved drugs (Hauser, Attwoodet al. , 2017; Insel, Sriram et al. , 2019). Around 15% of the ~350 non-sensory GPCRs are targets for therapeutic drugs but why do 85% of GPCRs remain untargeted by molecular therapies? One obvious answer is that many non-sensory GPCRs remain orphans with no known physiological agonists (Morfa, Bassoni et al. , 2018). Although GPR84 lacks a known physiological agonist it has been targeted in a number of randomised clinical trials. Other deorphanised GPCRs such as members of the chemokine receptor family that play a central role in inflammatory cell recruitment in pre-clinical models have proven difficult to target using small molecules (Schall & Proudfoot, 2011). However, recent FDA approval of a small molecule complement C5a receptor antagonist Avacopan for ANCA-associated vasculitis shows that this problem can be overcome with good medicinal chemistry, good target validation and appropriate financial incentive (Jayne, Merkel et al. , 2021).
While orphan GPCRs have long been considered an untapped source of new drugs, in his recent review Paul Insel argues that application of unbiased, hypothesis generating methodologies to quantify GPCR expression in cells and tissues (GPCRomics) can lead to the discovery of disease-relevant GPCRs that contribute to functional responses and pathophysiology (Insel, Sriram et al. , 2019). Application of GPCRomics to cancer cells and tumours may identify GPCRs following the example of CCR4 and may find application as potential biomarkers and maybe even therapeutic targets in cancer (Insel, Sriram et al. , 2018). Given the expression of GPR84 by macrophages it will be interesting to look at GPR84 expression by tumour associated macrophages in a range of solid tumours.

Orphan GPCRs and Class A GPCR deorphanisation

Approximately 30% of the ~400 non-olfactory human GPCRs have not been definitively paired with endogenous ligands and are hence designated as “orphan” receptors (S. P. H. Alexander, Christopouloset al. , 2019; Hauser, Gloriam et al. , 2020; Laschet, Dupuis et al. , 2018). During the ‘Golden Age’ of GPCR deorphanisation, which can be defined as the late 1990’s and early 2000s, endogenous agonists for approximately 10 GPCRs were identified every year. Pharmacology companies invested significant resources into ‘reverse pharmacology’ approaches to characterise GPCRs identified in the completed human genome sequence. Although the number of GPCR deorphanisations has fallen over the last decade there have been notable successes which owe much to the application of new strategies e.g. bioinformatics (Foster, Hauser et al. , 2019).
P2RY8 was recently deorphanised by searching for bioactive molecules in bile and culture supernatants of cell lines, revealing S-geranylgeranyl-L-glutathione as the agonist which regulates B cell confinement to germinal centres (Lu, Wolfreys et al. , 2019). The chemotactic peptide agonist for the T-cell receptor GPR15, GPR15L and encoded by C10ORF99 , was discovered following searches for open reading frames with similarity to chemokines, screening porcine colon tissue extracts for activity, and using comparative genomics and bioinformatics (Foster, Hauser et al. , 2019; Ocón, Pan et al. , 2017; Suply, Hannedouche et al. , 2017). On the other hand, numerous proposals have been made for the lipid agonist of GPR55, including its role as a putative third cannabinoid receptor or lysophosphatidic acid receptor, and has also been characterised as a chemotactic receptor for lysophosphatidylglucoside in monocytes and macrophages (X. Li, Hanafusa et al. , 2021).

Where to start looking for the true GPR84 ligand?

Consideration of recent successes in deorphanising Class A GPCRs might suggest new strategies to follow in the continuing hunt for endogenous agonists of the GPR84 receptor. So where should we start looking for the endogenous (or exogenous) GPR84 ligand(s)?
Expression profiling of murine Gpr84 mRNA conducted by our laboratory suggested expression in the atherosclerotic lesions ofApoE-/- mice, a result which should be confirmed using in situ RNA hybridisation or ideally immunohistochemistry (Recio, Lucy et al. , 2018). Perhaps fractionation of the modified lipids found in atherosclerotic lesions could identify novel lipid agonists, a strategy similar to that used to identify the P2RY8 ligand. Gpr84 mRNA expression by murine microglia suggest the CNS as a potential site of GPR84 ligands. Current medium chain fatty acid agonists do not exclude the possibility of protein or peptide agonists for the GPR84 receptor but without more spatial and disease related information it is hard to see how a similar strategy to that used to identify CARTp as the GPR160 ligand could be employed.
Finally, can we exclude an exogenous ligand as the true physiological agonist of GPR84? The evolutionary conservation of the GPR84 receptor in vertebrate but not avian species might support the idea of this Class A receptor in sensing pathogens or pathogen derived products (Schulze, Kleinau et al. , 2022). Schulze, Kleinau, et al . (2022) used cAMP inhibition assays of transiently transfected mammalian GPR84 orthologues to test the bacterial quorum sensing MCFAs cis -2-C10 and trans -2-C10. The authors’ cAMP signalling data revealed low potency activity. More recently, Peters, Rabe, et al . (2020) proposed 3-OH-C10 as a GPR84 signalling component of LPS and data showed an increase in 3-OH-C10 in stationary cultures of E. coli . Using M1 polarised THP-1 cells they demonstrated that 3-OH-C10 signalling via GPR84 involved Gα15 and p-Akt signalling.