Druggable Lipid GPCRs: Past, Present, and Prospects

G protein-coupled receptors (GPCRs) have seven transmembrane spanning domains and comprise the largest superfamily with ~800 receptors in humans. GPCRs are attractive targets for drug discovery because they transduce intracellular signaling in response to endogenous ligands via heterotrimeric G proteins or arrestins, resulting in a wide variety of physiological and pathophysiological responses. The endogenous ligands for GPCRs are highly chemically diverse and include ions, biogenic amines, nucleotides, peptides, and lipids. In this review, we follow the KonMari method to better understand druggable lipid GPCRs. First, we have a comprehensive tidying up of lipid GPCRs including receptors for prostanoids, leukotrienes, specialized pro-resolving mediators (SPMs), lysophospholipids, sphingosine 1-phosphate (S1P), cannabinoids, platelet-activating factor (PAF), free fatty acids (FFAs), and sterols. This tidying up consolidates 46 lipid GPCRs and declutters several perplexing lipid GPCRs. Then, we further tidy up the lipid GPCR-directed drugs from the literature and databases, which identified 24 clinical drugs targeting 16 unique lipid GPCRs available in the market and 44 drugs under evaluation in more than 100 clinical trials as of 2019. Finally, we introduce drug designs for GPCRs that spark joy, such as positive or negative allosteric modulators (PAM or NAM), biased agonism, functional antagonism like fingolimod, and monoclonal antibodies (MAbs). These strategic drug designs may increase the efficacy and specificity of drugs and reduce side effects. Technological advances will help to discover more endogenous lipid ligands from the vast number of remaining orphan GPCRs and will also lead to the development novel lipid GPCR drugs to treat various diseases.