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.