Analyses of orphan GPCRs' function in the pathogenesis of sepsis and their small-molecule therapeutics.

Sepsis is a systemic infection characterized by the dissemination of microbial pathogens through the bloodstream, and subsequently triggers inflammation, organ failure and concurrent immune suppression. The dysregulation of the innate and adaptive immune systems results in life-threatening organ failure or recurrent and often fatal infections. There are no effective and specific therapeutics due to the poorly understood underlying mechanisms. G-protein coupled receptors (GPCRs) are membrane-bound receptors that have emerged as important upstream regulators of immune system homeostasis and excessive inflammation, organ failure, and immune suppression in sepsis. Among GPCRs, orphan GPCRs are deficient of validated ligands and their function and therapeutics are underexplored. We critically discuss the functions of orphan GPCRs, especially GPR37, GPR43, GPR81 and GPR174 in sepsis. Activation of GPR37 and GPR43 is essential for enhanced phagocytic activity and diminished organ injury, thereby reducing mortality. Conversely, activation of GPR81 exacerbates sepsis through METTL3- and p300-mediated lung injury and increased endothelium permeability, while GPR174 promotes inflammation and increases mortality in septic rodents. In-depth analyses are conducted on the structure-based design, advantages and limitations of small-molecule orphan GPCR modulators, which indicate that GPR37 agonist artesunate and GPR43 agonist 4-CMTB are the most promising drug candidates for future optimization. We propose to design biased modulators that selectively activate orphan GPCR-coupled β-arrestin2, Gi, and Gq pathways, respectively, to enhance phagocytic activity and minimize inflammation. Taken together, specific orphan GPCR-coupled downstream signaling pathways present promising therapeutic targets for the treatment of sepsis.