FPR ligands comprise structurally very diverse
FPR ligands comprise structurally very diverse N-(p-amylcinnamoyl) mg of compounds, ranging from naturally occurring peptides/proteins or “danger signals” such as PAMPs and DAMPs (see 1.1), respectively, to endogenous lipids and even various synthetic non-peptides, such as benzimidazoles, pyrazolones, pyridazine-3(2H)-ones, and N-phenylurea derivatives. There are various excellent reviews on the ligands of FPRs available (for review [42,80,81] and references therein); we here briefly highlight the potential therapeutic value of the FPRs as druggable targets, and present a selection of ligands that might be important, especially with regard to the development of future innovative therapies for the treatment of infections and inflammatory conditions.
Summary and future perspectives There are first indications that the concept of biased agonism is also important for FPRs and can be applied for the development of novel FPR-based therapies (for review on biased agonism [, , ] and references therein) (see 2 Biased agonism, 3 FPR ligands, 4 , 5 Summary and future perspectives, Transparency document, , 2.3 Biased agonism and drug development). For instance, the activity profiles of two known small molecule agonists, i.e., Cmpd43 and Cmpd17b, have recently been compared for their applicability in the treatment of myocardial infarction, where inflammation has a significant contribution to the severity of the disease. Surprisingly, it turned out that the two compounds, which originally were described to be selective for agonists FPR1 or FPR2, respectively, are both dual agonists for FPR1 and FPR2 [, , , ]. Their signaling profile, however, differs substantially. Both compounds trigger extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt phosphorylation; signaling pathways, which are both cardioprotective when activated early at the onset of reperfusion. These pathways are therefore being targeted by most cardioprotective therapies. However, Cmpd17b mobilizes intracellular Ca2+ to a much lesser extent compared with Cmpd43. Most interestingly, Cmpd17b is cardioprotective in vivo and in vitro, while Cmpd43 is not . There are also first experimental observations that receptor oligomerization is common to the FPRs (Fig. 2). Bioluminescence and co-immunoprecipitation experiments have shown that FPR1 can homodimerize as well as interact with both FRP2 and FPR3 (see 2.4 Receptor oligomers – general considerations, 3.1 Synthetic W-peptides, 3.2 Pathogen-derived ligands, 3.3 Endogenous agonists, 3.4 FPR2 receptor agonists and neurodegeneration, 3.5 Anti-inflammatory signaling, 4.1 FPR KO models and bacterial/viral infection, 4.2 FPR KO models and tissue protection, 2.4.1 FPR receptors form homo and hetero oligomers) Therefore, both receptor homo- and hetero-oligomerization were observed and diversify cellular responses mediated via the FPR signaling axis [, , ]. It is not difficult to imagine that two or more interacting receptors alter the available conformational equilibrium for each GPCR and in turn the probability of intracellular effector interactions. Furthermore, specific ligand/receptor interactions might induce/select certain receptor conformations, which are (more or less) prone to homo- or heterodimerize (see below). In essence, these ligands then would predetermine the oligomeric state of GPCRs and in turn their actual pharmacological potential. In this context, it is worth mentioning that pro-resolving ligands AnxA1 (see 3.5.1), as well as its N-terminal peptide Ac2-26, evidently lead to an increased formation of FPR1/FPR2 heterodimers or FPR2 homodimers, while the pro-inflammatory agonist SAA and the antagonists CsH and WRW4 failed to do so. In addition, FPR2 oligomer stabilization seems to be linked to the activation of the p38/MAPKAPK/Hsp27 pathway [77,78]. In addition, receptor oligomerization might not be limited to only FPR family members but instead include even non-GPCR surface receptors, such as the scavenger receptor MARCO . Physical interactions between FPR1, FPR2, and MARCO have been demonstrated by bioluminescence and co-immunoprecipitation studies, and this was linked to agonist-evoked changes in cAMP levels and ERK1/2 phosphorylation .