Next Article in Journal
Human DNA Virus Exploitation of the MAPK-ERK Cascade
Next Article in Special Issue
Intragenic Antimicrobial Peptide Hs02 Hampers the Proliferation of Single- and Dual-Species Biofilms of P. aeruginosa and S. aureus: A Promising Agent for Mitigation of Biofilm-Associated Infections
Previous Article in Journal
Cross-Cell-Type Prediction of TF-Binding Site by Integrating Convolutional Neural Network and Adversarial Network
Previous Article in Special Issue
Alterations in Galanin-Like Immunoreactivity in the Enteric Nervous System of the Porcine Stomach Following Acrylamide Supplementation

Int. J. Mol. Sci. 2019, 20(14), 3426; https://doi.org/10.3390/ijms20143426

Review
Chemotactic Ligands that Activate G-Protein-Coupled Formylpeptide Receptors
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA
*
Author to whom correspondence should be addressed.
Received: 19 June 2019 / Accepted: 5 July 2019 / Published: 12 July 2019

Abstract

:
Leukocyte infiltration is a hallmark of inflammatory responses. This process depends on the bacterial and host tissue-derived chemotactic factors interacting with G-protein-coupled seven-transmembrane receptors (GPCRs) expressed on the cell surface. Formylpeptide receptors (FPRs in human and Fprs in mice) belong to the family of chemoattractant GPCRs that are critical mediators of myeloid cell trafficking in microbial infection, inflammation, immune responses and cancer progression. Both murine Fprs and human FPRs participate in many patho-physiological processes due to their expression on a variety of cell types in addition to myeloid cells. FPR contribution to numerous pathologies is in part due to its capacity to interact with a plethora of structurally diverse chemotactic ligands. One of the murine Fpr members, Fpr2, and its endogenous agonist peptide, Cathelicidin-related antimicrobial peptide (CRAMP), control normal mouse colon epithelial growth, repair and protection against inflammation-associated tumorigenesis. Recent developments in FPR (Fpr) and ligand studies have greatly expanded the scope of these receptors and ligands in host homeostasis and disease conditions, therefore helping to establish these molecules as potential targets for therapeutic intervention.
Keywords:
formyl peptide receptors; ligands; diseases

1. Properties of FPRs

Formylpeptide receptors (FPR, Fpr for expression in mice) are G-protein-coupled receptors and were incidentally the first GPCRs to be identified in neutrophils [1]. Though initially cloned from neutrophils, FPRs have since been identified in macrophages, endothelial cells, intestinal epithelial cells, fibroblasts, and others [2,3,4,5]. Humans possess three different forms of FPRs: FPR1, FPR2, and FPR3. FPR1 was the first named of the receptors, and it was initially discovered as the receptor for the formylated bacterial product formyl-methionine-leucyl-phenylalanine (fMLF), the name of which gave rise to the naming of the receptor in question [6]. FPR1 is most highly expressed in cells in the bone marrow and immune system, though it has some expression notable in cells of the lungs, brain, and gastrointestinal (GI) tract, among others [7,8]. FPR2 was the second discovered of these receptors, but it tends to be the more ubiquitously expressed of the two. The expression is primarily in cells of the bone marrow, immune system, GI tract, female organ tissues, and endocrine glands, though there are also some lower levels of expression in cells of the brain, liver, gallbladder, and pancreas [8,9]. There is little known about the biological significance of FPR3, and very little research has been done to elucidate its role. This receptor is mainly expressed in monocytes and dendritic cells but not neutrophils, and it resides in intracellular vesicles rather than on the cell surface like its counterpart receptors. FPR3, contrary to the other FPR variants, also has only one known endogenous peptide agonist [10,11].
The primary roles of FPRs involve cell chemotaxis in response to agonists, and new research has shown that they even contribute to direct phagocytosis of bacteria by neutrophils [12,13]. Activation of such receptors is also important for wound healing and gut development [14,15]. However, while FPRs were initially thought to only be responsible for neutrophil chemotaxis, FPR1 and FPR2 have both been shown to play pivotal roles in the progression of multiple diseases. For example, FPR2 may promote the malignancy of colon cancer, while FPR1 has similarly been tied to the progression of glioblastoma [16,17]. Conversely, FPR1 has demonstrated tumor suppressor functions in gastric cancer [18]. With such dual roles in cancer progression, it is clear that further mechanistic studies would contribute greatly to our understanding of FPRs, thus potentially leading to new therapeutics. While aberrant expression or activation of FPRs can be detrimental, somewhat contradictory findings demonstrate that constitutively active FPR was indispensable in the defense against the formation of biofilms by Candida albicans, as well as aggressive infiltration by Vibrio harveyi [19]. FPR-mediated cell activation does not solely include chemotactic and pro-inflammatory responses to pathogens, as activation also plays a very important role in the protection against other pathologies. Gobbetti et al. [20] demonstrated that Fpr2 confers protection against sepsis-mediated damage in mice. Furthermore, FPRs have been reported to mediate anxiety-related disorders and the resultant altered behaviors [21]. Lastly, a novel discovery for FPRs suggests that they act as mechanoreceptors in arteries, making them critical for proper arterial plasticity [22]. Given such diverse functions of these receptors, it should come as no surprise that FPRs respond to a plethora of ligands with diverse classifications.
While most FPR ligands induce cell chemotaxis, calcium flux, and even phagocytosis, they stimulate many other cell functions as well [23]. For instance, some ligands elicit inflammatory processes for the clearance of infection, recruitment of immune cells, etc. while other ligands activate pro-resolving, anti-inflammatory pathways. There are few chemoattractant GPCRs capable of transmitting both pro- and anti-inflammatory signals. This duality in FPR2 is initially determined by the nature of the ligands. Bacterial and mitochondrial formylated peptides are among those that classically activate a pro-inflammatory cell response to clear invaders and tissue damage, while Annexin A1 (Anx A1) and Lipoxin A4 (LXA4) are some of the better-known anti-inflammatory FPR2 ligands [24]. Cooray et al. [25] demonstrated that the switch between FPR2-mediated pro- and anti-inflammatory cell responses is due to conformational changes of the receptor upon ligand binding: binding of anti-inflammatory ligands such as Anx A1 caused FPRs to form homodimers, which led to the release of inflammation-resolving cytokines like IL-10. Conversely, inflammatory ligands such as serum-amyloid alpha (SAA) did not cause receptor homodimerization.
Though some of the diverse FPR (Fpr) ligands are small-molecules or non-peptides, the majority are small peptides that are either synthetic or natural with origins ranging from host and multicellular organisms to viruses and bacteria. These peptides have been extensively studied and patterns of recognized elements have begun to emerge. As is demonstrated below, the presence of formylated methionine in the peptide is generally an activator of FPR1, while FPR2 is less dependent upon this particular residue [26]. Expanding upon this, Bufe et al. [27] concluded that FPR recognition of bacterial peptides requires either a formylated methionine at the N-terminus or an amidated methionine at the C-terminus of a peptide, though they believe that as a general principle, the secondary structure rather than the primary sequence is important for recognition of the highly diverse ligands by FPR. One class of ligands which shall be shortly discussed is comprised of phenol-soluble modulins, and examination of these has led to the conclusion that FPR1 favors short, flexible structures while FPR2 has binding preference for longer peptides which are amphipathic in nature and may contain alpha helices [28]. The class of ligands mentioned above represents a small proportion of the known FPR agonists today, and this review will focus on formylated, microbe-derived, and mitochondrial peptides, as well as host and non-microbial, non-host peptides. Host-derived non-peptides, as well as synthetic or small-molecule ligands will also be discussed.

2. Formylated Peptides

The prototypic FPR ligand is fMLF, which was the first classified FPR agonist and also represents the shortest sequence to elicit a potent receptor response. While Fpr2 is generally considered the more promiscuous FPR, fMLF preferentially activates FPR1 with high affinity [29]. It has been shown that non-formylated bacterial peptides are much less potent than their formylated counterparts; a suggested reason for this is due to the use of formyl-methionine as a Gram-negative start codon, therefore marking a protein as pathogenic from the perspective of the host immune system [30]. There are many derivatives of fMLF which elicit FPR responses, many of which preferentially activate FPR2 rather than FPR1. Such derivatives include the peptide sequences fMLFII, fMLFIK, fMLFK, and fMLFW, among others [31]. Liu et al. [32] summarized many other formylated peptides that elicit responses through both FPR1 and FPR2, including f-MIFL, f-MIVIL, f-MIGWII, and f-MFEDAVAWF. Dozens of similar peptides have been isolated from equally numerous bacterial genera including Streptococcus, Haemophilus, Salmonella, Hydrogenobacter, Listeria, Neisseria, Staphylococcus, and others [27]. PSMα is another formylated peptide that has shown great efficacy in FPR activation. Thus far, the phenol-soluble modulins that have demonstrated a capacity for FPR activation include β2, α1, and α2, all of which are virulence factors isolated from Staphylococcus aureus. All three peptides activate FPR2, though the structural basis for activation remains unknown [33].
It is interesting to note that mammalian cell mitochondria, well-known for being bacterial in origin, also contain peptides that elicit FPR-mediated responses. However, while bacterial formylated peptides are considered pathogen-associated molecular patterns (PAMPs), the mitochondrial peptides are generally associated with cellular damage and are thus considered damage-associated molecular patterns (DAMPs) that elicit an inflammatory response [34]. These peptides, some of which include MMYALF, MFADRW, and Nle-LF-Nle-YK, have been tied to constriction of airways in the lungs, as well as neutrophil accumulation and other proinflammatory responses [35,36]. Likewise, lung diseases—including acute respiratory distress syndrome—have been found to have a higher presence of formylated mitochondrial peptides in bronchoalveolar lavage fluid, suggesting that lung inflammation is tightly tied to Fpr1 activation via these DAMPs [37]. Mitocryptide-2 (MCT-2) is another mitochondrial peptide. It is related to Cytochrome B of the electron transport chain and activates FPR2. Interestingly, while the N-terminal formylated methionine is entirely necessary for FPR2 activation by MCT-2, the carboxy-terminal residues are also important for receptor activation. Additionally, sequence analysis has revealed that the presence of the residues Thr7 and Ser8 can activate FPR2, though the peptides were most potent with Ile7 and Asn8 residues [38].
Another important mitochondrial peptide is the nicotinamide adenine dinucleotide (NADH) reductase subunit 1 (ND-1), which elicits a strong inflammatory response via FPR1 [39]. Bufe and Zufall [40] have successfully created a model that accurately predicts known mitochondrial peptide agonists for FPRs. Therefore, there is a strong likelihood for the discovery of many new mitochondrial, host-derived FPR agonist peptides. Another DAMP that elicits FPR-mediated responses is Mitochondrial Transcription Factor A (Tfam). While this necrosis-associated peptide has been previously shown to activate FPRs, activation does not appear to play a crucial role in the inflammatory responses of monocytic microglia in the brain; this may be due to lower FPR expression in this cell type [41,42]. The formylated peptide ligands for FPRs (Fprs) are listed in Table 1, and the mitochondrial peptides are listed in Table 2.

3. Microbe-Derived Peptides

Table 3 lists the microbe-derived FPR (Fprs) ligands. While formylated peptides first drew the attention of the scientific community to FPRs (Fprs), there are many other bacterial/viral peptides that are not necessarily formylated but which nevertheless elicit receptor responses. Although the majority of formylated microbial peptides preferentially activate FPR1, the preferred receptor for non-formylated peptides is FPR2 [26]. A large percentage of these non-formylated microbe-derived peptides are viral, and many of them are derived from the Human Immunodeficiency Virus (HIV) envelope proteins, including gp41 T20/DP178, gp41 T21/DP107, gp120 V3 loop, gp41 N36, gp120 F, and gp41 MAT-1 [44,45,46]. Despite the potential importance of FPRs in HIV research, very little work has been done to further explore this connection. However, Li et al. [47] demonstrated that persistent FPR activation desensitized host CCR5 and CXCR4 co-receptors to HIV proteins, thus reducing viral entry and subsequent replication. Still other viruses, including Hepatitis C Virus, HKU-1 coronavirus, and Herpes Simplex Virus, produce chemotactic ligands C5a, N-formyl HKU-1 coronavirus peptide, and gG-2p20, respectively, for FPR1 or FPR2 activation [48,49,50]. There is, however, some argument as to the efficacy of the Herpes Simplex viral peptide as an FPR agonist, as the overlapping sequence gG-2p19 was unable to definitively demonstrate that FPR activation played a significant role in the NK response to this virus [51].
Mills [49] used the sequence homology of T20/DP178 to further determine that the OC43 Coronavirus, 229E Coronavirus, NL36 Coronavirus, and even the Ebola Spike Protein were all peptides with aromatic-rich domains that elicited FPR-dependent cell activation. Interestingly, when examined from the context of the FPRs rather than the ligands, it was found that domain variability in the receptors determined ligand binding and subsequent cellular responses. This led to the conclusion that the variability of receptors among individuals might predispose or protect against certain viral infections, the susceptibility of which may be determined by receptor activation. In terms of non-viral and non-formylated microbe-derived peptides, there are few FPR agonists. Certain peptides from different strains of Enterococcus faecium have demonstrated FPR activation properties, though the ligand activity is not entirely predictable based on structure. Interestingly, E. faecium strains that are resistant to vancomycin contain potent FPR2 agonists, suggesting a potential role for FPR2 in antibiotic-resistant infections [52].

4. Host-Derived FPR Ligands

There are many different host-derived ligands that elicit strong FPR responses, though they have different biological implications. Misfolded proteins implicated in a variety of pathologies are one class of host-derived proteins eliciting FPR activation. Amyloid β-42 (Aβ-42), a peptide fragment well-documented in Alzheimer’s Disease (AD), interacts with FPR2. Additionally, part of FPR2’s role includes interaction with the Macrophage Receptor with Collagenous Structure (MARCO) scavenger receptor, which is responsible for reducing inflammation and alleviating inflammation-associated symptoms [60]. Interestingly, the symptoms that are viewed as a hallmark of AD are due to this same ligand binding an entirely different group of receptors which do not internalize them, therefore leading to an increased inflammatory pathology [61]. The prion peptide fragment, PrP106-126 also interacts with FPR2 on astrocytes and microglia, and the internalization of this peptide is detrimental to the host and contributes to disease progression [62]. Another neuropeptide that activates FPR2—though other studies claim it also activates FPR1—is the pituitary adenylate cyclase-activating polypeptide 27 (PACAP27), which has been shown to induce migration and Ca2+ mobilization, as well as upregulation of CD11b in neutrophils [63,64]. Another FPR agonist, the Vasoactive Intestinal Peptide (VIP), activates monocytes via FPR2 and may initiate an inflammation-resolving process [64,65].
Other host-derived FPR ligands are CKβ8-1 and the SHAAGtide sequence, as well as various uPAR domains from the Urokinase-Type 1 Plasminogen Activator Receptor (uPAR). CKβ8-1 is also known as the CCL23 chemokine, and it acts as an agonist for FPR2, along with its truncated N-terminal peptide called the SHAAGtide sequence that activates a chemokine GPCR [66,67]. It has been demonstrated that several uPAR peptides elicit FPR responses, including uPAR88-92, uPAR84-95, D2D3, and the SRSRYp sequence [68,69,70]. These sequences may foster the transition between fibroblasts to myofibroblasts, therefore increasing the pathology of fibrosis via FPR2 activation [68]. Another host-derived peptide, F2L, is derived from the N-terminus of the heme-binding protein, HEPB1. As the sole agonist specific for FPR3, F2L activates macrophages and possibly dendritic cells (DCs) as well [71]. However, other studies have demonstrated that FPR2 in neutrophils also exhibits a moderate affinity for F2L, though in this scenario F2L appears to have an inhibitory rather than a stimulatory effect [72,73]. A newer FPR ligand is Family with Sequence Similarity 3 (Member D), or FAM3D. This chemokine-like peptide is most highly expressed in the GI tract, though it is also expressed in cells of the immune system [8,74]. FAM3D has demonstrated a high affinity for both FPR1 and FPR2 and has been implicated in playing an important role in both inflammation and GI homeostasis via FPR activation [75]. Additional studies have found that FAM3D may also be involved in the beneficial role of glucagon secretion in Type 2 diabetes, as well as the detrimental development of abdominal aortic aneurysms [76,77].
In addition to endogenous peptides associated with cell-surface proteins and functional units, there are many ligands that are secreted by cells in response to tissue damage. Annexin-1 (AnxA1), also called Lipocortin-1, is an anti-inflammatory protein which is upregulated as a result of the stress responses of multiple host systems [78]. Some studies demonstrate AnxA1 to be an FPR1 agonist, while others show it as an FPR2 agonist; hence, it likely activates both. One study demonstrated its role in the attenuation of rheumatoid arthritis symptoms by decreasing fibroblast-like synoviocyte proliferation via FPR2 [79]. However, another study showed that AnxA1 initiated autocrine signaling in breast cancer via FPR1 and led to an increase in tumor growth and metastasis [80]. Additionally, the absence of AnxA1 has been tied to increased disease severity in both rheumatoid arthritis and obstructive pulmonary disease, leading to the hypothesis that treatment with exogenous AnxA1 may help reduce symptoms associated with different inflammatory pathologies [81,82]. In addition to AnxA1, multiple derivatives of the parent protein, including Ac1-25, Ac2-26, and Ac9-25, activate FPR2 [83,84,85]. These peptides have protective effects in ischemia-induced lung injury and atherosclerosis [84,86]. As with its pro-survival property, AnxA1 acts as a double-edged sword: secretion of either AnxA1 or Ac2-26 by tumor-associated fibroblasts induces the acquisition of stem-like features in prostate cancer cells, thus leading to a worse prognosis [87].
Serum-amyloid alpha (SAA) is an endogenous FPR2 agonist secreted by liver or macrophages in response to inflammatory stress and, more notably, tissue damage. In endothelial cells, SAA enhances the expression and activity of Tissue Factor—a protein necessary for clotting and wound repair—while additionally inhibiting the activity of Tissue Factor Pathway Inhibitor. Both functions were demonstrated to be the result of FPR2 activation [88]. SAA, via FPR2 activation, additionally increases the production of the wound-healing chemokine, CCL2, by vascular endothelial cells [89]. More recent studies have demonstrated the role of an SAA-FPR2 axis in neovascularization in the cornea as well [90,91].
Human LL-37 is an antimicrobial peptide that induces Cxcl13 and Tnfsf13b transcription, as well as B cell activation and proliferation via FPR2. It also contributes to the maintenance of B-cell germinal centers in Peyer’s Patches of the gut [92]. LL-37 also promotes the growth of both colorectal and ovarian cancer cells [93,94]. The murine homologue of LL-37, Cathelicidin-related antimicrobial peptide (CRAMP), is similarly an Fpr2 agonist and has been shown to promote atherosclerosis and DC maturation [95,96]. CRAMP also plays a pivotal role in maintaining the homeostasis of the colon mucosa and microbiota balance, demonstrating its potential as a therapeutic molecule [97]. The list of host-derived FPR (Fpr) ligands is shown in Table 4.

5. Synthetic Peptides and Non-Peptide Small Molecules

By far the most extensive category of FPR ligands includes the synthetic and small-molecule ligands, of which there are over 40 currently known, as shown in Table 5. W-peptides are among the better-known synthetic peptides acting as FPR agonists, and they include the sequences WKYMVm-NH2, WKYMVM-NH2, as well as many derivatives. Bufe et al. [27] demonstrated that both FPR1 and FPR2 mediate Ca2+ mobilization responses in leukocytes to more than 20 different combinations and derivatives of the W-peptide. A breakdown of the data suggests that certain residues in the peptide sequence are more important than others: C3 tyrosine, C4 methionine, and C6 D-methionine are all required for ligand activity, as is the carboxy-terminal NH2. Peptides may additionally be shortened on the N-terminus by two amino acids or elongated by three amino acids before FPR activation capacity is severely diminished. While the applications of WKYMV-sequences have been little explored, one recent study showed that the activation of FPR2 by WKYMVm may enhance the homing of endothelial cells, thus improving tissue healing, especially in ischemic neovasculogenesis in injured limbs [3]. Interestingly, another study showed that WKYMVm was capable of desensitizing HIV coreceptors CXCR4 and CCR5, therefore decreasing the entry of HIV-1 into macrophages and CD4+ T cells [47].
M-peptides are another subclass of synthetic/peptide library isolates and include MMK-1 and MMWLL. MMK-1, an FPR2 agonist, is by far the more commonly used peptide, and studies have shown that it may be useful as an anti-anxiety drug, as well as a drug to counteract hair loss from chemotherapy [98,104]. However, there has been some concern about its use in certain drug regimens, as it may amplify the response of monocytes to SIO2-coated nanoparticles, making it an important player in calculating the proper dosing when using such nanoparticles [105]. MMWLL is another M-peptide specific for FPR1. It is not classically a formylated peptide, though the addition of a formylated methionine induces a more potent FPR1 response than even the classic prototypic fMLF [106]. A much newer class of synthetic peptides are the FPR1-agonistic AApeptides, based on the general structure of N-acylated-N-aminoethyl amino acid residues. There are three different AApeptide subgroups called the α-peptides, α-AApeptides, and γ-AApeptide, all of which have different R-groups at the designated α or γ position. Most of these derivatives of AApeptides induce Ca2+ mobilization in rat basophil leukemia (RBL) cells transfected with human FPR1, though the γ-AApeptide Compound 7 at 10 μM elicited a more potent cell response than fMLF at the same concentration, making it a reasonably high-affinity ligand for FPR1 at this concentration, though not at lower concentrations [107]. See Table 5 for all synthetic peptides.
Some newer, non-peptide synthetic compounds being studied are various derivatives of ureidopropanamide molecules. They have demonstrated a capacity for protection against LPS-induced microglial death via an FPR2-dependent pathway, and pre-treatment with concentrations as low as 1 μM showed the protective effects [24]. Thus, these ligands show promising potential as treatment for diseases associated with inflammation in the Central Nervous System (CNS). Another pro-resolving synthetic ligand is the quinazolinone derivative Quin-C1. It is an Fpr2 agonist and has been shown to be effective at reducing inflammatory cytokines and clearing neutrophils and lymphocytes in murine models of lung injury [114]. Schepetkin et al. [115] demonstrated that three different synthetic molecules are agonists for both FPR1 and FPR2. Two of these are bombesin-related BB1/BB2 antagonists called PD168368 and PD176252, and they induce Ca2+ flux as well as neutrophil degranulation with EC50 values in the nanomolar range, thus making them potent FPR agonists. The third agonist is the Cholecystokinin-1 receptor agonist A-71623, which exhibits FPR1 and FPR2 agonism, though with a much higher EC50. In structural studies, these ligands were cross-reactive with FPR1/2 and possessed both Trp and N-phenylurea moieties. This led to the hypothesis that the combination of moieties greatly increases the chance that an agonist will activate both receptors.
Kirpotina et al. [116] screened over 6000 compounds and isolated nearly 30 different FPR1 and/or FPR2 agonists, all of which are derivatives of acetohydrazide, 2-(N-piperazinyl)acetamide, N’-phenylurea, and benzimidazole. The acetohydrazide derivatives (compounds AG-07/7, AG-09/92, AG-09/96, AG-09/101, and AG-09/102) and N-phenylurea derivatives (AG-09/3, AG-09/4, AG-09/73 through AG-09/77, and AG-09/82) are all FPR2-specific, though the acetohydrazide compounds tend to have lower efficacies on average. Also, the benzimidazole derivatives are either FPR1-specific (AG-09/1, AG-09/2, AG-09/13, AG-09/18, AG-09/19, and AG-09/21) or are agonists for both FPR1 and FPR2 (AG-09/16, AG-09/17, AG-09/20, and AG-09/22 through AG-09/24); no FPR2-specific benzimidazole derivatives have yet been identified. Pyridazines are another class of non-peptide, synthetic molecules which can have many different derivatives. Currently, only two compounds have been identified as potent mixed FPR1 and FPR2 agonists with an EC50 of around 2 μM each. These two compounds are referred to as compounds 8b and 8c with the Pyridazin-3(2H)-one structure. Additionally, they have R substitutions of SCH3 and OCH3, as well as R1 substitutions of I and SCH3, respectively. Both R and R1 substitutions are on substituted benzene rings [117]. (See Table 6 for the list of synthetic/small molecule non-peptide agonists).

6. Ligands from Non-Human Sources

As the search for disease treatments continues, many investigators have turned to developing compounds isolated from various plants and animals for potential therapeutic uses. Some of these new compounds have been shown to activate human or murine FPRs. The first of these is a series of compounds isolated from the centipede Scolopendra subspinipes mutilans, which has classically been used in Oriental medicine and is now being studied for therapeutic potential [126]. New studies show that compounds Scolopendrasin III and V both cause human neutrophil migration via FPR1, while Scolopendrasin IX seems to work through FPR2 to promote neutrophil chemotaxis. The two former compounds have not yet been studied for effectiveness against particular pathologies, though Compound IX has traditionally been an effective treatment for rheumatoid arthritis in Oriental medicine. New evidence confirms this activity, citing the activation of FPR2 as the mechanism [9,127]. Temporins are another class of FPR agonists and consist of antimicrobial peptides isolated from the Rana Temoraria frogs. Temporin A and Rana-6 are two such peptides, and both activate FPR2 to promotion leukocyte migration. There are also two distinct synthetic peptides, I4S10-C and I4G10-C, that are modeled after temporins and activate FPR2 [128].
Rubimetide is a peptide (Met-Arg-Trp) isolated from the digest of Rubisco in spinach. While it has been studied for some time, it has just recently been classified as an FPR2 agonist and has further demonstrated an ability to produce anxiolytic-like effects, thus alleviating some symptoms associated with anxiety [98]. The same investigators also isolated soymetide from the α’ subunit of β-conglycinin from soybeans and then demonstrated its activity as an FPR1 agonist [129]. Furthermore, the antimicrobial peptides Piscidin-1 and -3, which were isolated from fish, have been shown to induce myeloid cell chemotaxis via both FPR1 and FPR2. As a testament to the harms of water pollution by metals, this study also demonstrated that conjugation of Cu2+ with either of these compounds reduces the chemotactic activity of mammalian neutrophils [130] (See Table 7 for the list of peptides from other non-human sources).

7. Concluding Remarks

FPRs are a class of seven-transmembrane, G-protein-coupled receptors (GPCRs) that interact with a remarkably diverse range of ligands. As demonstrated, these ligands may originate from pathogens, the host, the synthetic peptide or compound library, or even non-host multicellular organisms. With such diverse agonist binding capacity, it is not surprising that FPRs may be either detrimental or beneficial in different pathophysiological conditions. Though the majority of these agonists have been known for more than a decade, newer studies are finding novel roles for these ligands in treatments for conditions ranging from anxiety and mental health disorders to arthritis and wounds. The field of FPR agonist studies has demonstrated the potential of these molecules to have therapeutic mechanisms useful for medicine. In addition to the vast number of agonists summarized here, there are also extensive lists of antagonistic ligands that may also provide protective mechanisms in various diseases [23,44]. Thus, further exploration of FPRs and ligands as therapeutic targets would be highly beneficial to diseases including cancer, sceptic shock, arthritis, and many other inflammatory pathologies.

Funding

This project has been funded in part by Federal funds from the National Cancer Institute (NCI), National Institutes of Health (NIH), under Contract No. HSN261200800001E, and is also supported in part by the Intramural Research Program of NCI, NIH.

Acknowledgements

The authors thank Cheri Rhoderick for secretarial assistance.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Dorward, D.; Lucas, C.; Chapman, G.; Haslett, C.; Dhaliwal, K.; Rossi, A. The role of formylated peptides and formyl peptide receptor 1 in governing neutrophil function during acute inflammation. Am. J. Pathol. 2015, 185, 1172–1184. [Google Scholar] [CrossRef] [PubMed]
  2. Le, Y.; Murphy, P.; Wang, J. Formyl-peptide receptors revisited. Trends Immunol. 2002, 23, 541–548. [Google Scholar] [CrossRef]
  3. Heo, S.; Kwon, Y.; Jang, I.; Jeong, G.; Yoon, J.; Kim, C.; Kwon, S.; Bae, Y.; Kim, J. WKYMVm-induced activation of formyl peptide receptor 2 stimulates ischemic neovasculogenesis by promoting homing of endothelial colony-forming cells. Stem Cells 2014, 32, 779–790. [Google Scholar] [CrossRef] [PubMed]
  4. Kim, M.; Min, S.; Park, Y.; Kim, J.; Ryu, S.; Bae, Y. Expression and functional role of formyl peptide receptor in human bone marrow-derived mesenchymal stem cells. FEBS Lett. 2007, 581, 1917–1922. [Google Scholar] [CrossRef] [PubMed]
  5. Van Compernolle, S.; Clark, K.; Rummel, K.; Todd, S. Expression and function of formyl peptide receptors on human fibroblast cells. J. Immunol. 2003, 171, 2050–2056. [Google Scholar] [CrossRef] [PubMed]
  6. Boulay, F.; Tardif, M.; Brouchon, L.; Viganis, P. Synthesis and use of a novel N-formyl peptide derivative to isolate a human N-formyl peptide receptor cDNA. Biochem. Biophys. Res. Commun. 1990, 168, 1103–1109. [Google Scholar] [CrossRef]
  7. V18.1.proteinatlas.org. FPR1 Tissue Expression. Available online: https://www.proteinatlas.org/ENSG00000171051-FPR1/tissue (accessed on 19 May 2019).
  8. Uhlen, M.; Fagerberg, L.; Hallstrom, B.; Lindskog, C.; Oksvold, P.; Mardinoglu, A.; Sivertsson, A.; Kampf, C.; Sjostedt, E.; Asplund, A.; et al. Proteomics. Tissue-based map of the human proteome. Science 2015, 347, 1260419. [Google Scholar] [CrossRef] [PubMed]
  9. V18.1.proteinatlas.org. FPR2 Tissue Expression. Available online: https://www.proteinatlas.org/ENSG00000171049-FPR2/tissue (accessed on 19 May 2019).
  10. Rabiet, M.; Macari, L.; Dahlgren, C.; Boulay, F. N-formyl peptide receptor 3 (FPR3) departs from the homologous FPR2/ALD receptor with regard to the major processes governing chemoattractant receptor regulation, expression at the cell surface, and phosphorylation. J. Biol. Chem. 2011, 286, 26718–26731. [Google Scholar] [CrossRef] [PubMed]
  11. Kim, S.; Jim, J.; Jo, S.; Lee, H.; Lee, S.; Shim, J.; Seo, S.; Yun, J.; Bae, Y. Functional expression of formyl peptide receptor family in human NK cells. J. Immunol. 2009, 183, 5511–5517. [Google Scholar] [CrossRef] [PubMed]
  12. Wen, X.; Xu, X.; Sun, W.; Chen, K.; Pan, W.; Wang, J.; Bolland, S.; Jin, T. G-protein-coupled formyl peptide receptors play a dual role in neutrophil chemotaxis and bacterial phagocytosis. Mol. Biol. Cell 2019, 30, 346–356. [Google Scholar] [CrossRef]
  13. Wang, W.; Li, T.; Wang, X.; Yuan, W.; Cheng, Y.; Zhang, H.; Xu, E.; Zhang, Y.; Shi, S.; Ma, D.; et al. FAM19A4 is a novel cytokine ligand of formyl peptide receptor 1 (FPR1) and is able to promote the migration and phagocytosis of macrophages. Cell Mol. Immunol. 2015, 12, 615–624. [Google Scholar] [CrossRef]
  14. Liu, M.; Chen, K.; Yoshimura, T.; Liu, Y.; Gong, W.; Le, Y.; Gao, J.; Zhao, J.; Wang, J.; Wang, A. Formylpeptide receptors mediate rapid neutrophil mobilization to accelerate wound healing. PLoS ONE 2014, 9, e90613. [Google Scholar] [CrossRef]
  15. Chen, K.; Liu, M.; Liu, Y.; Yoshimura, T.; Shen, W.; Le, Y.; Durum, S.; Gong, W.; Wang, C.; Gao, J.; et al. Formylpeptide receptor-2 contributes to colonic epithelial homeostasis, inflammation, and tumorigenesis. J. Clin. Investig. 2013, 123, 1694–1704. [Google Scholar] [CrossRef]
  16. Xiang, Y.; Yao, X.; Chen, K.; Wang, X.; Zhou, J.; Gong, W.; Yoshimura, T.; Huang, J.; Wang, R.; Wu, Y.; et al. The G-protein coupled chemoattractant receptor FPR2 promotes malignant phenotype of human colon cancer cells. Am. J. Cancer Res. 2016, 6, 2599–2610. [Google Scholar]
  17. Snapkov, I.; Oqvist, C.; Figenschau, Y.; Kogner, P.; Johnsen, J.; Sveinbjornsson, B. The role of formyl peptide receptor 1 (FPR1) in neuroblastoma tumorigenesis. BMC Cancer 2016, 16, 490. [Google Scholar] [CrossRef]
  18. Prevete, N.; Liotti, F.; Visciano, C.; Marone, G.; Melillo, R.; de Paulis, A. The formyl peptide receptor 1 exerts a tumor suppressor function in human gastric cancer by inhibiting angiogenesis. Oncogene 2005, 34, 3826–3838. [Google Scholar] [CrossRef]
  19. Sedlmayer, F.; Hell, D.; Muller, M.; Auslander, D.; Fussenegger, M. Designer cells programming quorum-sensing interference with microbes. Nat. Commun. 2019, 9. [Google Scholar] [CrossRef]
  20. Gobbetti, T.; Coldewey, S.; Chen, J.; McArthur, S.; le Faouder, P.; Cenac, N.; Flower, R.; Thiemermann, C.; Perretti, M. Nonredundant protective properties of FPR2/ALX in polymicrobial murine sepsis. Proc. Natl. Acad. Sci. USA 2014, 111, 18685–18690. [Google Scholar] [CrossRef]
  21. Gallo, I.; Rattazzi, L.; Piras, G.; Gobbetti, T.; Panza, E.; Perretti, M.; Dalley, J.; D’acquisto, F. Formyl peptide receptor as a novel therapeutic target for anxiety-related disorders. PLoS ONE 2014, 9, e114626. [Google Scholar] [CrossRef]
  22. Wenceslau, C.; McCarthy, C.; Szasz, T.; Calmasini, F.; Mamenko, M.; Webb, R. Formyl peptide receptor-1 activation exerts a critical role for the dynamic plasticity of arteries via actin polymerization. Pharm. Res. 2019, 141, 276–290. [Google Scholar] [CrossRef]
  23. He, H.; Ye, R. The formyl peptide receptors: Diversity of ligands and mechanism for recognition. Molecules 2017, 22, 455. [Google Scholar] [CrossRef]
  24. Stama, M.; Oelusarczyk, J.; Lacivita, E.; Kirpotina, L.; Schepetkin, I.; Chamera, K.; Riganti, C.; Perrone, R.; Quinn, M.; Basta-Kaim, A.; et al. Novel ureidopropanamide based N-formyl peptide receptor 2 (FPR2) agonists with potential application for central nervous system disorders characterized by neuroinflammation. Eur. J. Med. Chem. 2017, 141, 703–720. [Google Scholar] [CrossRef]
  25. Cooray, S.; Gobbetti, T.; Montero-Melendez, T.; McArthur, S.; Thompson, D.; Clark, A.; Flower, R.; Perretti, M. Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses. Proc. Natl. Acad. Sci. USA 2013, 110, 18232–18237. [Google Scholar] [CrossRef]
  26. Winther, M.; Holdfeldt, A.; Gabl, M.; Wang, J.; Forsman, H.; Dahlgren, C. Formylated MHC Class Ib binding peptides activate both human and mouse neutrophils primarily through formyl peptide receptor 1. PLoS ONE 2016, 11, e0167529. [Google Scholar] [CrossRef]
  27. Bufe, B.; Schuman, T.; Kappl, R.; Bogeski, I.; Kummerow, C.; Podgorska, M.; Smola, S.; Hoth, M.; Zufall, F. Recognition of bacterial signal peptides by mammalian formyl peptide receptors: A new mechanism for sensing pathogens. J. Biol. Chem. 2015, 290, 7369–7387. [Google Scholar] [CrossRef]
  28. Kretschmer, D.; Rautenberg, M.; Linke, D.; Peschel, A. Peptide length and folding state govern the capacity of staphylococcal B-type phenol-soluble modulins to activate human formyl-peptide receptors 1 or 2. J. Leukoc. Biol. 2015, 97, 689–697. [Google Scholar] [CrossRef]
  29. Marasco, W.; Phan, S.; Krutzsch, H.; Showell, H.; Feltner, D.; Nairn, R.; Becker, E.; Ward, P. Purification and identification of formyl-methionyl-leucyl-phenylalanine as the major peptide neutrophil chemotactic factor produced by Escherichia coli. J. Biol. Chem. 1984, 259, 5430–5439. [Google Scholar]
  30. Piatkov, K.; Vu, T.; Hwang, C.; Varshavsky, A. Formyl-methionine as a degradation signal at the N-termini of bacterial proteins. Microb. Cell 2015, 2, 376–393. [Google Scholar] [CrossRef]
  31. He, H.; Troksa, E.; Caltabioano, G.; Pardo, L.; Ye, R. Structural determinants for the interaction of formyl peptide receptor 2 with peptide ligands. J. Biol. Chem. 2014, 289, 2295–2306. [Google Scholar] [CrossRef]
  32. Liu, Y.; Chen, K.; Wang, J. Chapter 91: FPR Ligands. In Handbook of Biologically Active Peptides, 2nd ed.; Kastin, A., Ed.; Elsevier Inc.: San Diego, CA, USA, 2013; pp. 671–680. [Google Scholar]
  33. Towle, K.; Lohans, C.; Miskolzie, M.; Acedo, J.; van Belkum, M.; Vedaras, J. Solution structures of phenol-soluble modulins a1, a2, B2, virulence factors from Staphylococcus aureus. Biochemistry 2016, 55, 4798–4806. [Google Scholar] [CrossRef]
  34. Zhang, Q.; Raoof, M.; Chen, Y.; Sumi, Y.; Sursal, T.; Wolfgang, J.; Broki, K.; Itagaki, K.; Hauser, C. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 2010, 464, 104–107. [Google Scholar] [CrossRef]
  35. Wenceslau, C.; Szasz, T.; McCarthy, C.; Baban, B.; NeSmith, E.; Webb, R. Mitochondrial N-formyl peptides cause airway contraction and lung neutrophil infiltration via formyl peptide receptor activation. Pulm. Pharmacol. 2016, 37, 49–56. [Google Scholar] [CrossRef]
  36. Zhang, X.; Wang, T.; Yuan, Z.; Dai, L.; Zeng, N.; Wang, H.; Liu, L.; Wen, F. Mitochondrial peptides cause proinflammatory responses in the alveolar epithelium via FPR-1, MAPKs, and AKT: A potential mechanism involved in acute lung injury. Am. J. Physiol. Lung Cell Mol. Physiol. 2018, 315, L775–L786. [Google Scholar] [CrossRef]
  37. Dorward, D.; Lucas, C.; Doherty, M.; Chapman, G.; Scholefield, E.; Morris, A.; Felton, J.; Kipari, T.; Humphries, D.; Robb, C.; et al. Novel role for endogenous mitochondrial formylated peptide-driven formyl peptide receptor 1 signaling in acute respiratory distress syndrome. Respir. Res. 2017, 72, 928–936. [Google Scholar]
  38. Lind, S.; Gabl, M.; Holdfeldt, A.; Martensson, J.; Sundqvist, M.; Nishino, K.; Dahlgren, C.; Mukai, H.; Forsman, H. Identification of residues critical for FPR2 activation by the cryptic peptide mitocryptide-2 originating from the mitochondrial DNA-encoded cytochrome b. J. Immunol. 2019, ji1900060. [Google Scholar] [CrossRef]
  39. Shawar, S.; Rich, R.; Becker, E. Peptides from the amino-terminus of mouse mitochondrially encoded NADH dehydrogenase subunit 1 are potent chemoattractants. Biochem. Biophys. Res. Commun. 1995, 211, 812–818. [Google Scholar] [CrossRef]
  40. Bufe, B.; Zufall, F. The sensing of bacteria: Emergin principles for the detection of signal sequences by formyl peptide receptors. Biomol. Concepts 2016, 7, 205–214. [Google Scholar] [CrossRef]
  41. Little, J.; Simtchouk, S.; Schindler, S.; Villanueva, E.; Gill, N.; Walker, D.; Wolthers, K.; Klergis, A. Mitochondrial transcription factor A (Tfam) is a pro-inflammatory extracellular signaling molecule recognized by brain microglia. Mol. Cell Neurosci. 2014, 60, 88–96. [Google Scholar] [CrossRef]
  42. Wencesclau, C.; McCarthy, C.; Szasz, T.; Spitler, T.; Goulopoulou, S.; Webb, R.; DAMPs in Cardiovascular Disease Working Group. Mitochondrial damage-associated molecular patterns and vascular function. Eur. Heart J. 2014, 35, 1172–1177. [Google Scholar] [CrossRef]
  43. Oie, C.; Snapkov, I.; Elvevold, K.; Sveinbjornsson, B.; Smedsrod, B. FITC conjugation markedly enhances hepatic clearance of N-formyl peptides. PLoS ONE 2016, 11, e0160602. [Google Scholar] [CrossRef]
  44. Wang, J.; Chen, K. Chemotactic Peptide Ligands for Formylpeptide Receptors Influencing Inflammation. In Handbook of Biologically Active Peptides; Kastin, A., Ed.; Elsevier Inc.: San Diego, CA, USA, 2006; pp. 547–552. [Google Scholar]
  45. Braun, M.; Wang, J.; Lahey, E.; Rabin, R.; Kelsall, B. Activation of the formyl peptide receptor by the HIV-derived peptide T-20 suppresses interleukin-12 p70 production by human monocytes. Blood 2001, 97, 3531–3536. [Google Scholar] [CrossRef] [PubMed]
  46. Wood, M.; Cole, A.; Eade, C.; Chen, L.; Chai, K.; Cole, A. The HIV-1 gp41 ectodomain is cleaved by matriptase to produce a chemotactic peptide that acts through FPR2. Immunology 2014, 142, 474–483. [Google Scholar] [CrossRef]
  47. Li, B.; Wetzel, M.; Mikovits, J.; Henderson, E.; Rogers, T.; Gong, W.; Le, Y.; Ruscetti, F.; Wang, J. The synthetic peptide WKYMVm attenuates the function of the chemokine receptors CCR5 and CXCR4 through activation of formyl peptide receptor-like 1. Blood 2001, 97, 2941–2947. [Google Scholar] [CrossRef] [PubMed]
  48. Lin, Q.; Fang, D.; Hou, X.; Le, Y.; Fang, J.; Wen, F.; Gong, W.; Chen, K.; Wang, J.; Su, S. HCV peptide(C5a), an amphipathic a-helical peptide of hepatitis Virus C, is an activator of N-formyl receptor in human phagocytes. J. Immunol. 2011, 186, 2087–2094. [Google Scholar] [CrossRef]
  49. Mills, J.S. Peptides derived from HIV-1, HIV-2, Ebola virus, SARS coronavirus and coronavirus 229E exhibit high affinity binding to the formyl peptide receptor. Biochim. Biophys. Acta 2006, 1762, 693–703. [Google Scholar] [CrossRef]
  50. Bellner, L.; Thoren, F.; Nygren, E.; Liljeqvist, J.; Karlsson, A.; Eriksson, K. A proinflammatory peptide from herpes simplex virus type 2 glycoprotein G affects neutrophil, monocyte, and NK cell functions. J. Immunol. 2005, 174, 2235–2241. [Google Scholar] [CrossRef] [PubMed]
  51. Bellner, L.; Karlsson, J.; Fu, H.; Boulay, F.; Dahlgren, C.; Eriksson, K.; Karlsson, A. A monocyte-specific peptide from herpes simplex virus type 2 glycoprotein G activates the NADPH-oxidase but not chemotaxis through a G-protein-coupled receptor distinct from the members of the formyl peptide receptor family. J. Immunol. 2007, 179, 6080–6087. [Google Scholar] [CrossRef]
  52. Bloes, D.; Otto, M.; Peschel, A.; Kretschmer, D. Enterococcus faecium stimulates human neutrophils via the formyl-peptide receptor 2. PLoS ONE 2012, 7, e39910. [Google Scholar] [CrossRef]
  53. Betten, A.; Bylund, J.; Christophe, T.; Boulay, F.; Romero, A.; Hellstrand, K.; Dahlgren, C. A proinflammatory peptide from Helicobacter pylori activates monocytes to induce lymphocyte dysfuntion and apoptosis. J. Clin. Investig. 2001, 108, 1221–1228. [Google Scholar] [CrossRef]
  54. Su, S.; Gao, J.; Gong, W.; Dunlop, N.; Murphy, P.; Oppenheim, J.; Wang, J. T21/DP107, a synthetic leucine zipper-like domain of the HIV-1 envelope gp41, attracts and activates human phagocytes by using G-protein-coupled formyl peptide receptors. J. Immunol. 1999, 162, 5924–5930. [Google Scholar]
  55. Shen, W.; Proost, P.; Li, B.; Gong, W.; Le, Y.; Sargeant, R.; Murphy, P.; Van Damme, J.; Wang, J. Activation of the chemotactic peptide receptor FPRL1 in monocytes phosphorylates the chemokine receptor CCR5 and attenuates cell responses to selected chemokines. Biochem. Biophys. Res. Commun. 2000, 272, 276–283. [Google Scholar] [CrossRef] [PubMed]
  56. Le, Y.; Jiang, S.; Hu, J.; Gong, W.; Su, S.; Dunlop, N.; Shen, W.; Li, B.; Wang, J. N36, a synthetic N-terminal heptad repeat domain of the HIV-1 envelope protein gp41, is an activator of human phagocytes. Clin. Immunol. 2000, 96, 236–242. [Google Scholar] [CrossRef] [PubMed]
  57. Deng, X.; Ueda, H.; Su, S.; Gong, W.; Dunlop, N.; Gao, J.; Ruscetti, F.; Murphy, P.; Wang, J. A synthetic peptide derived from human immunodeficiency virus type 1 gp120 downregulates the expression and function of chemokine receptors CCR5 and CXCR4 in monocytes by activating the 7-transmembrane G-protein-coupled receptor FPRL1/LXA4R. Blood 1999, 94, 1165–1173. [Google Scholar] [PubMed]
  58. Le, Y.; Yazawa, H.; Gong, W.; Yu, Z.; Ferrans, V.; Murphy, P.; Wang, J. The neurotoxic prion peptide fragment PrP(106-126) is a chemotactic agonist for the G protein-coupled receptor formyl peptide receptor-like1. J. Immunol. 2001, 166, 1448–1451. [Google Scholar] [CrossRef] [PubMed]
  59. Tcherniuk, S.; Cenac, N.; Comte, M.; Frouard, J.; Errazuriz-Cerda, E.; Galabov, A.; Morange, P.; Vergnolle, N.; Si-Tahar, M.; Alessi, M.; et al. Formyl peptide receptor 2 plays a deleterious role during influenza A virus infection. J. Infect. Dis. 2016, 214, 237–247. [Google Scholar] [CrossRef] [PubMed]
  60. Brandenburg, L.; Konrad, M.; Wruck, C.; Koch, T.; Lucius, R.; Pufe, T. Functional and physical interactions between formyl-peptide-receptors and the scavenger MARCO and their involvement in amyloid beta 1-42-induced signal transduction in glial cells. J. Neurochem. 2010, 113, 749–760. [Google Scholar] [CrossRef] [PubMed]
  61. Jarosz-Griffiths, H.; Noble, E.; Rushworth, J.; Hooper, N. Amyloid-B receptors: The good, the bad, and the prion protein. J. Biol. Chem. 2016, 291, 3174–3183. [Google Scholar] [CrossRef]
  62. Brandenburg, L.; Koch, T.; Sievers, J.; Ralph, L. Internalization of PrP(106-126) by the formyl-peptide-receptor-like-1 in glial cells. J. Neurochem. 2006, 101, 718–728. [Google Scholar] [CrossRef]
  63. Kim, Y.; Lee, B.; Kim, O.; Bae, Y.; Lee, T.; Suh, P.; Ryu, S. Pituitary adenylate cyclase-activating polypeptide 27 is a functional ligand for formyl peptide receptor-like 1. J. Immunol. 2006, 176, 2669–2675. [Google Scholar] [CrossRef]
  64. Chedid, P.; Boussetta, T.; Dang, P.; Belambri, S.; Marzaioli, V.; Fasseau, M.; Walker, F.; Couvineau, A.; El-Benna, J.; Marie, J. Vasoactive intestinal peptide dampens formyl-peptide-induced ROS production and inflammation by targeting a MAPK-p47phox phosphorylation pathway in monocytes. Mucosal Immunol. 2017, 10, 332–340. [Google Scholar] [CrossRef]
  65. Carion, T.; Kracht, D.; Strand, E.; David, E.; McWhirter, C.; Ebrahim, A.; Berger, E. VIP modulates the ALX/FPR2 receptor axis toward inflammation resolution in a mouse model of bacterial keratitis. Prostag. Other Lipid Mediat. 2019, 140, 18–25. [Google Scholar] [CrossRef]
  66. Elagoz, A.; Henderson, D.; Babu, P.; Salter, S.; Grahames, C.; Bowers, L.; Roy, M.; Laplante, P.; Grazzini, E.; Ahmad, S.; et al. A truncated form of CKβ8-1 is a potent agonist for human formyl peptide-receptor-like 1 receptor. Br. J. Pharmacol. 2004, 141, 37–46. [Google Scholar] [CrossRef] [PubMed]
  67. Ye, R.; Boulay, F.; Wang, J.; Dahlgren, C.; Gerard, C.; Parmentier, M.; Serhan, C.; Murphy, P. International union of basic and clinical pharmacology. LXXIII. Nomenclature for the formyl peptide receptor family. Pharm. Rev. 2009, 61, 119–161. [Google Scholar] [CrossRef]
  68. Rossi, F.; Napolitano, F.; Pesapane, A.; Mascolo, M.; Staibano, S.; Matucci-Cericinic, M.; Guiducci, S.; Ragno, P.; di Spigna, G.; Pistiglione, L.; et al. Upregulation of the N-formyl peptide receptors in Scleroderma Fibroblasts fosters the switch to myofibroblasts. J. Immunol. 2015, 194, 5161–5173. [Google Scholar] [CrossRef]
  69. De Paulis, A.; Montuori, N.; Prevete, N.; Fiorentino, I.; Rossi, F.; Visconte, V.; Rossi, G.; Marone, G.; Ragno, P. Urokinase induces basophil chemotaxis through a urokinase receptor epitope that is an endogenous ligand for formyl peptide receptor-like 1 and -like 2. J. Immunol. 2004, 173, 5739–5748. [Google Scholar] [CrossRef]
  70. Gargiulo, L.; Longanesi-Cattani, I.; Bifulco, K.; Franco, P.; Raiola, R.; Campiglia, P.; Grieco, P.; Peluso, G.; Stoppelli, P.; Carriero, M. Cross-talk between fMLP and vitronectin receptors triggered by urokinase receptor-derived SRSRY peptide. J. Biol. Chem. 2005, 280, 25225–25232. [Google Scholar] [CrossRef]
  71. Devosse, T.; Dutoit, R.; Migeotte, I.; De Nadai, P.; Imbault, V.; Communi, D.; Salmon, I.; Parmentier, M. Processing of HEBP1 by chathepsin D gives rise to F2L, the agonist of formyl peptide Receptor 3. J. Immunol. 2011, 187, 1475–1485. [Google Scholar] [CrossRef] [PubMed]
  72. Gao, J.; Guillabert, A.; Hu, J.; Le, Y.; Urizar, E.; Seligman, E.; Fang, K.; Yuan, X.; Imbault, V.; Communi, D.; et al. F2L, a peptide derived from heme-binding protein, chemoattracts mouse neutrophils by specifically activating Fpr2, the low-affinity N-formylpeptide receptor. J. Immunol. 2007, 178, 1450–1456. [Google Scholar] [CrossRef]
  73. Lee, S.; Lee, M.; Lee, H.; Kim, S.; Shim, J.; Jo, S.; Lee, J.; Kim, J.; Choi, Y.; Baek, S.; et al. F2L, a peptide derived from heme-binding protein, inhibits LL-37-induced cell proliferation and tube formation in human umbilical vein endothelial cells. FEBS Lett. 2008, 582, 273–278. [Google Scholar] [CrossRef] [PubMed]
  74. V18.1.proteinatlas.org. FAM3D Tissue Expression. Available online: https://www.proteinatlas.org/ENSG00000198643-FAM3D/tissue (accessed on 28 May 2019).
  75. Peng, X.; Xu, E.; Liang, W.; Pei, X.; Chen, D.; Zheng, D.; Zhang, Y.; Zheng, C.; Wang, P.; She, S.; et al. Identification of FAM3D as a new endogenous chemotaxis agonist for the formyl peptide receptors. J. Cell Sci. 2016, 129, 1831–1842. [Google Scholar] [CrossRef]
  76. Cao, T.; Yang, D.; Zhang, W.; Wang, Y.; Qiao, Z.; Gao, L.; Liang, Y.; Yu, B.; Zhang, P. FAM3D inhibits glucagon secretion via MKP1-dependent suppression of ERK1/2 signaling. Cell Biol. Toxicol. 2015, 33, 457–466. [Google Scholar] [CrossRef]
  77. He, L.; Fu, Y.; Deng, J.; Shen, Y.; Wang, Y.; Yu, F.; Xie, N.; Chen, Z.; Hong, T.; Peng, X.; et al. Deficiency of FAM3D (Family with sequence similarity 3, member D), a novel chemokine, attenuates neutrophil recruitment and ameliorates abdominal aortic aneurysm development. Arter. Thromb. Vas. 2018, 38, 1616–1631. [Google Scholar] [CrossRef] [PubMed]
  78. Buckingham, J.; Flower, R. Annexin A1. In Stress: Neuroendocrinology and Neurobiology: Handbook of Stress Series; Fink, G., Ed.; Elsevier Inc.: Parkville, Australia, 2013; Volume 2, pp. 257–263. [Google Scholar]
  79. Odobasic, D.; Jia, Y.; Kao, W.; Fan, H.; Wei, X.; Gu, R.; Ngo, D.; Kitching, A.; Hodsworth, S.; Morand, E.; et al. Formyl peptide receptor activation inhibits the expansion of effector T cells and synovial fibroblasts and attenuates joint injury in models of rheumatoid arthritis. Int. Immunopharmacol. 2018, 61, 140–149. [Google Scholar] [CrossRef] [PubMed]
  80. Vecchi, L.; Zoia, M.; Santos, T.; Beserra, A.; Ramos, C.; Colombo, B.; Maia, Y.; Andrade, V.; Mota, S.; Araujo, T.; et al. Inhibition of the AnxA1/FPR1 autocrine axis reduces MDA-MB-231 breast cancer cell growth and aggressiveness in vitro and in vivo. BBA-Mol. Cell Res. 2018, 1865, 1368–1382. [Google Scholar] [CrossRef]
  81. Kao, W.; Gu, R.; Jia, Y.; Wei, X.; Fan, H.; Harris, J.; Zhang, Z.; Quinn, J.; Morand, E.; Yang, Y. A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis. Br. J. Pharmacol. 2014, 171, 4087–4096. [Google Scholar] [CrossRef] [PubMed]
  82. Chen, Y.; Lin, M.; Lee, C.; Liu, S.; Wang, C.; Fang, W.; Chao, T.; Wu, C.; Wei, Y.; Chang, H.; et al. Defective formyl peptide receptor 2/3 and annexin A1 expression associated with M2a polarization of blood immune cells in patients with chronic obstructive pulmonary disease. J. Transl. Med. 2018, 16, 69. [Google Scholar] [CrossRef]
  83. Lange, C.; Starrett, D.; Goetsch, J.; Gerke, V.; Rescher, U. Transcriptional profiling of human monocytes reveals complex changes in the expression pattern of inflammation-related genes in response to the annexin A1-derived peptide Ac1-25. J. Leukoc. Biol. 2007, 82, 1592–1604. [Google Scholar] [CrossRef]
  84. Liao, W.; Wu, S.; Wu, G.; Pao, H.; Tang, S.; Huang, K.; Chu, S. Ac2-26, an Annexin A1 peptide, attenuates ischemia-repurfusion-induced acute lung injury. Int. J. Mol. Sci. 2017, 18, 1771. [Google Scholar] [CrossRef]
  85. Karlsson, J.; Fu, H.; Boulay, F.; Dahlgren, C.; Hellstrand, C.; Hellstrand, K.; Movitz, C. Neutrophil NADPH-oxidase activation by an annexin A1 peptide is transduced by the formyl peptide receptor (FPR), whereas an inhibitory signal is generated independently of the FPR family receptors. J. Leukoc. Biol. 2005, 78, 761–762. [Google Scholar] [CrossRef]
  86. Fredman, G.; Kamaly, N.; Spolitu, S.; Milton, J.; Ghorpade, D.; Chiasson, R.; Kuriakose, G.; Perretti, M.; Farokzhad, O.; Tabas, I. Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice. Sci. Transl. Med. 2015, 7, 275ra. [Google Scholar] [CrossRef]
  87. Geary, L.; Nash, K.; Adisetiyo, H.; Liang, M.; Liao, C.; Jeong, J.; Zandi Em Roy-Burman, P. CAF-secreted annexin A1 induces prostate cancer cells to gain stem cell-like features. Mol. Cancer Res. 2014, 12, 607–612. [Google Scholar] [CrossRef] [PubMed]
  88. Zhao, Y.; Zhou, S.; Heng, C. Impact of serum amyloid A on tissue factor and tissue factor pathway inhibitor expression and activity in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 2007, 27, 1645–1650. [Google Scholar] [CrossRef]
  89. Lee, H.; Kim, S.; Shim, J.; Kim, H.; Yun, J.; Baek, S.; Kim, K.; Bae, Y. A pertussis toxin sensitive G-protein-independent pathway is involved in serum amyloid A-induced formyl peptide receptor 2-mediated CCL2 production. Exp. Mol. Med. 2010, 42, 302–309. [Google Scholar] [CrossRef]
  90. Hinrichs, B.; Matthews, J.; Siuda, D.; O’Leary, M.; Wolfarth, A.; Saeedi, B.; Nusrat, A.; Neish, A. Serum Amyloid A1 is an epithelial prorestitutive factor. Am. J. Pathol. 2018, 188, 937–949. [Google Scholar] [CrossRef] [PubMed]
  91. Ren, S.; Qi, X.; Jia, C.; Wang, Y. Serum amyloid A and pairing formyl peptide receptor 2 are expressed in corneas and involved in inflammation-mediated neovascularization. Int. J. Opthalmol. 2014, 7, 187–193. [Google Scholar]
  92. Kim, S.; Kim, Y.; Jang, Y. Cutting edge: LL-37-mediated formyl peptide receptor-2 signaling in follicular dendritic cells contributes to B cell activation in Peyer’s Patch germinal centers. J. Immunol. 2017, 198, 629–633. [Google Scholar] [CrossRef]
  93. Pan, X.; Quan, W.; Wu, J.; Xiao, W.; Sun, Z.; Li, D. Antimicrobial peptide LL-37 in macrophages promotes colorectal cancer growth. Zhonghua Zhong Liu Za Zhi 2018, 40, 412–417. [Google Scholar] [PubMed]
  94. Chen, X.; Zhou, X.; Qi, G.; Tang, Y.; Guo, Y.; Si, J.; Liang, L. Roles and mechanisms of human cathelicidin LL-37 in cancer. Cell Physiol. Biochem. 2018, 47, 1060–1073. [Google Scholar] [CrossRef]
  95. Doring, Y.; Drechsler, M.; Wantha, S.; Kemmerich, L.; Lievens, D.; Vijayan, S.; Gallo, R.; Weber, C.; Soehnlein, O. Lack of neutrophil-derived CRAMP reduces atherosclerosis in mice. Circ. Res. 2012, 110, 1052–1056. [Google Scholar] [CrossRef]
  96. Chen, K.; Xiang, Y.; Huang, J.; Gong, W.; Yoshimura, T.; Jiang, Q.; Tessarollo, L.; Le, Y.; Wang, J. The formylpeptide receptor 2 (Fpr2) and its endogenous ligand cathelin-related antimicrobial peptide (CRAMP) promote dendritic cell maturation. J. Biol. Chem. 2014, 289, 17553–17563. [Google Scholar] [CrossRef] [PubMed]
  97. Yoshimura, T.; McLean, M.; Dzutsev, A.K.; Yao, X.; Chen, K.; Huang, J.; Gong, W.; Zhou, J.; Ziang, Y.; Badger, J.; et al. The antimicrobial peptide CRAMP is essential for colon homeostasis by maintaining microbiota balance. J. Immunol. 2018, 200, 2174–2185. [Google Scholar] [CrossRef] [PubMed]
  98. Zhao, H.; Sonada, S.; Yoshikawa, A.; Ohinata, K.; Yoshikawa, M. Rubimetide, humanin, and MMK1 exert anxiolytic-like activities via the formyl peptide receptor 2 in mice followed by the successive activation of DP1, A2A, and GABAA receptors. Peptides 2016, 83, 16–20. [Google Scholar] [CrossRef] [PubMed]
  99. Kamal, A.; Hayhoe, R.; Paramasivam, A.; Cooper, D.; Flower, R.; Solito, E.; Perretti, M. Antiflammin-2 activates the human formyl-peptide receptor like 1. Sci. World J. 2006, 6, 1375–1384. [Google Scholar] [CrossRef] [PubMed]
  100. Sun, R.; Iribarren, P.; Zhang, N.; Zhou, Y.; Gong, W.; Cho, E.; Lockett, S.; Chertov, O.; Bednar, F.; Rogers, T.; et al. Identification of neutrophil granule protein cathepsin G as a novel chemotactic agonist for the G protein-coupled formyl peptide receptor. J. Immunol. 2004, 173, 428–436. [Google Scholar] [CrossRef] [PubMed]
  101. Corminboeuf, O.; Leroy, X. FPR2/ALXR agonists and the resolution of inflammation. J. Med. Chem. 2015, 58, 5689–5701. [Google Scholar] [CrossRef] [PubMed]
  102. Dean, S.; Wang, C.; Nam, K.; Maruyama, C.; Trump, B.; Baker, O. Aspirin triggered resolvin D1 reduces inflammation and restores saliva secretion in a Sjogrens syndrome mouse model. Rheumatology 2019, 58, 1285–1292. [Google Scholar] [CrossRef] [PubMed]
  103. Guo, Z.; Hu, Q.; Xu, L.; Guo, Z.; Ou, Y.; He, Y.; Yin, C.; Sun, X.; Tang, J.; Zhang, J. Lipoxin A4 reduces inflammation through formyl peptide receptor 2/p38MAPK signaling pathway in subarachnoid hermorrhage rats. Stroke 2016, 47, 490–497. [Google Scholar] [CrossRef]
  104. Tsuruki, T.; Yoshikawa, M. Orally administered FPRL1 receptor agonist peptide MMK-1 inhibits etoposide-induced alopecia by a mechanism different from intraperitoneally administered MMK-1. Peptides 2006, 27, 820–825. [Google Scholar] [CrossRef]
  105. Tavano, R.; Segat, D.; Fedeli, C.; Malachin, G.; Lubian, E.; Mancin, F.; Papini, E. Formyl-peptide receptor agonists and amorphous SiO2-NPs synergistically and selectively increase the inflammatory responses of human monocytes and PMNs. Nanobiomedicine 2016, 3. [Google Scholar] [CrossRef]
  106. Chen, J.; Bernstein, H.; Chen, M.; Wang, L.; Ishii, M.; Turck, C.; Coughlin, S. Tethered ligand library for discovery of peptide agonists. J. Biol. Chem. 1995, 270, 23398–23401. [Google Scholar] [CrossRef]
  107. Hu, Y.; Cheng, N.; Wu, H.; Kang, S.; Ye, R.; Cai, J. Design, synthesis and characterization of fMLF-mimicking AApeptides. ChemBioChem 2014, 15, 2420–2426. [Google Scholar] [CrossRef] [PubMed]
  108. Hecht, I.; Rong, J.; Sampaio, A.; Hermesh, C.; Rutledge, C.; Shemesh, R.; Toporik, A.; Beiman, M.; Dassa, L.; Niv, H.; et al. A novel peptide agonist of Formyl-peptide receptor-like 1 (ALX) displays anti-inflammatory and cardioprotective effects. J. Pharmacol. Exp. 2009, 328, 426–434. [Google Scholar] [CrossRef] [PubMed]
  109. Gabl, M.; Holdfeldts, A.; Winther, M.; Oprea, T.; Bylund, J.; Dahlgren, C.; Forsman, H. A pepducin designed to modulate P2Y2R function interacts with FPR2 in human neutrophils and transfers ATP to an NADPH-oxidase-activating ligand through a receptor cross-talk mechanism. BBA Cell Biol. 2016, 1863, 1228–1237. [Google Scholar]
  110. Winther, M.; Dahlgren, C.; Forsman, H. Formyl peptide receptors in mice and men: Similarities and differences in recognition of conventional ligands and modulating lipopeptides. Basic Clin. Pharmacol. Toxicol. 2017, 122, 191–198. [Google Scholar] [CrossRef] [PubMed]
  111. Bae, G.; Lee, H.; Jung, Y.; Shim, J.; Kim, S.; Baek, S.; Kwon, J.; Park, J.; Bae, Y. Identification of novel peptides that stimulate human neutrophils. Exp. Mol. Med. 2012, 44, 130–137. [Google Scholar] [CrossRef] [PubMed]
  112. Holdfeldt, A.; Svovbakke, S.; Winther, M.; Gabl, M.; Nielsen, C.; Perez-Gassol, I.; Larsen, C.; Wang, J.; Karlsson, A.; Dahlgren, C.; et al. The lipidated peptidomimetic Lau-((S)-Aoc)-(Lys-Bnphe)6-NH2 is a novel formyl peptide receptor 2 agonist that activates both human and mouse neutrophil NADPH oxidase. J. Biol. Chem. 2016, 291, 19888–19899. [Google Scholar] [CrossRef] [PubMed]
  113. Madenspacher, J.; Azzam, K.; Gong, W.; Gowdy, K.; Vitek, M.; Laskowitz, D.; Remaley, A.; Wang, J.; Fessler, M. Apolipoproteins and apolipoprotein mimetic peptides modulate phagocyte trafficking through chemotactic activity. J. Biol. Chem. 2012, 287, 43730–43740. [Google Scholar] [CrossRef] [PubMed]
  114. He, M.; Cheng, N.; Gao, W.; Zhang, M.; Zhang, Y.; Ye, R.; Wang, M. Characterization of Quin-C1 for its anti-inflammatory property in a mouse model of bleomycin-induced lung injury. Acta Pharm. Sin. 2011, 32, 601–610. [Google Scholar] [CrossRef] [PubMed]
  115. Schepetkin, I.; Kirpotina, L.; Khlebnikov, A.; Jutila, M.; Quinn, M. Gastrin-releasing peptide-neuromedin B receptor antagonist PD176252, PD168368, and related analogs are potent agonists of human formyl-peptide receptors. Mol. Pharm. 2011, 79, 77–90. [Google Scholar] [CrossRef]
  116. Kirpotina, L.; Khlebnikov, A.; Schepetkin, I.; Ye, R.; Rabiet, M.; Jutila, M.; Quinn, M. Identification of novel small-molecule agonists for human formyl peptide receptors and pharmacophore models of their recognition. Mol. Pharm. 2010, 77, 159–170. [Google Scholar] [CrossRef]
  117. Crocetti, L.; Vergelli, C.; Cilibrizzi, A.; Graziano, A.; Khlebnikov, A.; Kirpotina, L.; Schepetkin, I.; Quinn, M.; Giovannoni, M. Synthesis and pharmacological evaluation of new pyridazine-based thioderivatives as formyl peptide receptor (FPR) agonists. Drug Dev. Res. 2013, 74. [Google Scholar] [CrossRef]
  118. Frohn, M.; Xu, H.; Zou, X.; Chang, C.; McElvaine, M.; Plant, M.; Wong, M.; Tagari, P.; Hungate, R.; Burli, R. New ‘chemical probes’ to examine the role of the hFPRL1 (or ALXR) receptor in inflammation. Bioorg. Med. Chem. Lett. 2007, 17, 6633–6637. [Google Scholar] [CrossRef] [PubMed]
  119. Cilibrizzi, A.; Schepetkin, I.; Bartolucci, G.; Crocetti, L.; Dal Piaz, V.; Giovannoni, M.; Graziano, A.; Kirpotina, L.; Quinn, M.; Vergelli, C. Synthesis, enantioresolution, and activity profile of chiral 6-methyl-2,4-disubstituted pyridazine-3(2H)-ones as potent N-formyl peptide receptor agonists. Bioorg. Med. Chem. 2012, 20, 3781–3792. [Google Scholar] [CrossRef] [PubMed]
  120. Pinilla, C.; Edwards, B.; Appel, J.; Yates-Gibbins, T.; Giulanotti, M.; Medina-Franco, J.; Young, S.; Santos, R.; Sklar, L.; Houghten, R. Selective agonists and antagonists of formylpeptide receptors: Duplex flow cytometry and mixture-based positional scanning libraries. Mol. Pharmacol. 2013, 84, 314–324. [Google Scholar] [CrossRef] [PubMed]
  121. Lacivita, E.; Schepetkin, I.; Stama, M.; Kirpotina, L.; Colabufo, N.; Perrone, R.; Khlebnikov, A.; Quinn, M.; Leopoldo, M. Novel 3-(1H-Indol-3-yl)-2-[3-(4-nitrophenyl)ureido]propanamides as selective agonists of human formyl-peptide receptor 2. Bioorg. Med. Chem. 2014, 23, 3913–3924. [Google Scholar] [CrossRef] [PubMed]
  122. Lee, H.; Bae, Y. The anti-infective peptide, innate defense-regulator peptide, stimulates neutrophil chemotaxis via a formyl peptide receptor. Biochem. Biophys. Res. Commun. 2008, 369, 573–578. [Google Scholar] [CrossRef] [PubMed]
  123. Nijnik, A.; Madera, L.; Ma, S.; Waldbrook, M.; Elliott, M.; Easton, D.; Mayer, M.; Mullaly, S.; Kindrachuk, J.; Jenssen, H.; et al. Synthetic cationic peptide IDR-1002 provides protection against bacterial infections through chemokine induction and enhanced leukocyte recruitment. J. Immunol. 2010, 184, 2539–2550. [Google Scholar] [CrossRef] [PubMed]
  124. Qin, C.; May, L.; Li, R.; Cao, N.; Rosli, S.; Deo, M.; Alexander, A.; Horlock, D.; Bourke, J.; Yang, Y.; et al. Small-molecule-biased formyl peptide receptor agonist compound 17b protects against myocardial ischaemia-reperfusion injury in mice. Nat. Commun. 2017, 8, 14232. [Google Scholar] [CrossRef] [PubMed]
  125. Cilibrizzi, A.; Quinn, M.; Kirpotina, L.; Schepetkin, I.; Holderness, J.; Ye, R.; Rabiet, M.; Biancalani, C.; Cesari, N.; Graziano, A.; et al. 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones: A novel class of small-molecule agonists for formyl peptide receptors. J. Med. Chem. 2009, 52, 5044–5057. [Google Scholar]
  126. Hakim, M.; Yang, S.; Lai, R. Centipede venoms and their components: Resources for potential therapeutic applications. Toxins 2015, 7, 4832–4851. [Google Scholar] [CrossRef] [PubMed]
  127. Park, Y.; Park, B.; Lee, M.; Jeong, S.; Lee, H.; Sohn, D.; Song, J.; Lee, J.; Hwang, J.; Bae, Y. A novel antimicrobial peptide acting via formyl peptide receptor 2 shows therapeutic effects against rheumatoid arthritis. Sci. Rep. 2018, 8, 14664. [Google Scholar] [CrossRef] [PubMed]
  128. Chen, Q.; Wade, D.; Kurosaka, K.; Wang, Z.; Oppenheim, J.; Yang, D. Temporin A and related frog antimicrobial peptides use formyl peptide receptor-like 1 as a receptor to chemoattract phagocytes. J. Immunol. 2004, 173, 2652–2659. [Google Scholar] [CrossRef] [PubMed]
  129. Tsuruki, T.; Kishi, K.; Takahashi, M.; Tanaka, M.; Matsukawa, T.; Yoshikawa, M. Soymetide, an immunostimulating peptide derived from soybean β-conglycinin, is an fMLP agonist. FEBS Lett. 2003, 540, 206–210. [Google Scholar] [CrossRef]
  130. Kim, S.; Zhang, F.; Gong, W.; Chen, K.; Xia, K.; Liu, F.; Fross, R.; Wang, J.; Linhardt, R.; Cotton, M. Copper regulates the interactions of antimicrobial piscidin peptides from fish mast cells with formyl peptide receptors and heparin. J. Biol. Chem. 2018, 293, 15381–15396. [Google Scholar] [CrossRef] [PubMed]
  131. Park, Y.; Lee, S.; Jung, Y.; Lee, M.; Lee, H.; Lee, H.; Park, J.; Koo, J.; Koo, J.; Bae, Y. Promotion of formyl peptide receptor 1-mediated neutrophil chemotactic migration by antimicrobial peptides isolated from the centipede Scolopendra subspinipes mutilans. BMB Rep. 2016, 49, 520–525. [Google Scholar] [CrossRef] [PubMed]
Table 1. Formylated bacterial peptide agonists for formylpeptide receptors (FPRs) (Fprs).
Table 1. Formylated bacterial peptide agonists for formylpeptide receptors (FPRs) (Fprs).
AgonistClassificationReceptorCitation
MLF FPR1[29]
MIFL FPR1, FPR2[32]
MIVIL FPR1, FPR2
MIGWI FPR1, FPR2
MIVTLF FPR1, FPR2
MIGWII FPR1, FPR2
MFEDAVAWF FPR1, FPR2
MLFK (-II, -IK, -K, -W) FPR2[31]
Streptococcus f-MGFFIS FPR1, FPR2[27]
bacillus f-MKNFKG FPR 2
Salmonella f-MAMKKL FPR 1
Haemophilus f-MVMKFK FPR1, FPR2
Psychrosomonas f-MLFYFS FPR1, FPR2
Desulotomaculum f-MLFYLA FPR1, FPR2
Borrelia f-MLKKVY FPR1, FPR2
Vibrio F-MVKIIF FPR1, FPR2
Clostridium f-MKKNLV FPR 2
Streptomyces f-MVPISI FPR1, FPR2
Hydrogenobacter MKKFLL FPR 2
Listeria MKKIML FPR1, FPR2
Desulfovibrio MKFCTA FPR1, FPR2
Neisseria MKTSIR FPR1, FPR2
Staphylococcus MFIYYCK FPR 1
f-NLPNTL FPR 1[43]
PSMα peptides β2, α1, and α2Staphylococcus aureusFPR 2[33]
Table 2. Mitochondrial peptide ligands for FPRs (Fprs).
Table 2. Mitochondrial peptide ligands for FPRs (Fprs).
AgonistClassificationReceptorCitation
MMYALFFormylatedFPR 2[35]
MLKIVformylatedFPR 2
MYFINILTLFormylatedFPR 2
MFADRWFormylatedFPR 2
Nle-LF-Nle-YK FPR 2
Mitocryptide-2 [MCT-2]Cytochrome BFPR 2[38]
ND1NADH reductase subunit 1FPR1[39]
TFamMitochondrial Transcription factorFPR1[41]
Table 3. Microbe-derived peptide ligands for FPRs (Fprs).
Table 3. Microbe-derived peptide ligands for FPRs (Fprs).
AgonistClassificationReceptorCitation
Hp2-20HelicobacterFPR2[53]
T20/DP178HIV gp41FPR1[45]
T21/DP107HIV gp41FPR1, FPR2[54]
V3 peptideHIV Gp 120FPR2[55]
N36 peptideHIV Gp 41FPR2[56]
F peptideHIV Gp 120FPR2[57]
MAT-1HIV gp41FPR2[46]
gG-2p20Herpes Simplex VirusFPR1[50]
N-formyl HKU-1 coronavirus peptideHKU-1 virusFPR1[49]
Listeria peptides FPR1[26]
Enterococcus faecium proteins FPR2[52]
PrP106-126 FPR2[58]
C5a HCV peptideHep C VirusFPR2[48]
OC43 coronavirus proteinOC43 CoronovirusUnknown[49]
229E Coronavirus protein229E CoronavirusUnknown
NL36 Coronavirus proteinNL36 CoronavirusUnknown
Spike ProteinEbola virusUnknown
Influenza A VirusAnnexin A1 surface proteinFPR2[59]
Table 4. Host-derived FPR (Fpr) ligands and their classification.
Table 4. Host-derived FPR (Fpr) ligands and their classification.
AgonistClassificationReceptorCitation
CKβ 8-1 [human CCL23]CCL23 chemokineFPR2[66]
SHAAGtideCKβ 8-1FPR2
Humanin FPR2[98]
F2LHeme binding proteinFPR2, FPR3[71,72,73]
SAA FPR2[90]
Annexin 1/ Lipocortin 1 FPR2[78]
Ac1-25Annexin 1FPR2[83]
Ac2-26Annexin 1FPR2[84]
Ac9-25Annexin 1FPR2[85]
Antiflammin-2 (AF-2) FPR2[99]
Aβ-42Amyloid peptideFPR2[60]
D2D3Urokinase receptorFPR2[70]
SRSRYpUrokinase receptorFPR2
LL-37Antimicrobial peptideFPR2[92]
PrP106–126Prion proteinFPR2[62]
PACAP27Pituitary adenylate cyclaseFPR2, FPR1[63,64]
uPAR88-92Urokinase receptorFPR2[68]
uPAR84-95Urokinase receptorFPR2, FPR3[69]
Cathepsin G FPR1[100]
FAM3DChemokine-likeFPR1, FPR2[75]
FAM19A4Chemokine-likeFPR1[13]
ATLXA4 acetylsalicyclic acid-triggeredArachidonic acid derivativeFPR2[101]
Resolvin D1 (RvD1) and aspirin-triggered RvD1Specialized pro-resolving lipid mediatorFPR2[102]
Vasoactive intestinal protein FPR2[65]
Lipoxin-A4/Apsirin-triggered lipoxinsFatty AcidFPR2[103]
Table 5. Synthetic peptide ligands for FPRs (Fprs).
Table 5. Synthetic peptide ligands for FPRs (Fprs).
AgonistClassificationReceptorCitation
AApeptidesα-peptides, α-AApeptides, and γ-AApeptideN-acylated-N-aminoethyl amino acid residueFPR1[107]
CGEN-855ATIPMFVPESTSKLQKFTSWFM-amideFPR2[108]
P2Y2PalIC2 pepducinP2Y2R pepducinFPR2[109]
F2Pal10FPR2 pepducinFPR2[110]
GMMWAIGly-Met-Met-Trp-Ala-Ile-CONH2FPR1[111]
Lau-[[S]-Aoc]-[Lys-Bnphe]6-NH2Lipidated peptomimetic peptideFPR2[112]
L-37pAApoA-I mimetic peptideFPR2[113]
MMHWFMMet-Met-His-Trp-Phe-Met-CONH2FPR1[111]
MMHWAMMet-Met-His-Trp-Ala-Met-CONH2FPR2[111]
MMK-1Peptide libraryFPR2[98]
MMWLLPeptide libraryFPR1[106]
WKYMVm(-NH2)Peptide libraryFPR1, FPR2[27]
WKYMVMPeptide libraryFPR1, FPR2
F2Pal16FPR2 PepducinFPR2[110]
Table 6. Small/molecule compounds functioning as FPR (Fpr) agonists.
Table 6. Small/molecule compounds functioning as FPR (Fpr) agonists.
AgonistClassificationReceptorCitation
Quin-C1Quinazolinone derivativeFPR2[114]
N-substituted benzimidazole 11 FPR2[118]
Compound 8aPyridazin-3(2H)-one derivative 1FPR1, FPR2[117]
Compound 8bPyridazin-3(2H)-one derivative 2FPR1, FPR2
Chiral pyridazines6-methyl-2,4-disubstituted pyridazine-3(2H)-onesFPR1 [weak], FPR2[119]
PD176252Bombesin-related BB1/BB2 antagonistFPR1, FPR2[115]
PD168368Bombesin-related BB1/BB2 antagonistFPR1, FPR2
A-71623Cholescystokinin-1 receptor agonistFPR1, FPR2
1753-103Synthetic libraryFPR1[120]
Compound (S)-17 Ureidopropanamide derivative
(S)-3-(4-cyanophenyl)-N-((1-(3-chloro4-fluorophenyl]cyclopropyl]methyl)-2-(3-(4-fluorophenyl)ureido)propaniamide ((S)-17)
FPR2[24]
1754-49Synthetic libraryFPR2[120]
(S)-9a3-(1H-Indol-3-yl)-2-(3-(4-nitrophenyl)ureido)propenamide derivativeFPR2[121]
IDR1KSRIVPAIPVSLL-NH2FPR1[122]
IDR-1002VQRWLIVWRIRK-NH2FPR2-uncertain[123]
AG-09/1, AG-09/2, AG-09/13, AG-09/18, AG-09/19, and AG-09/21Benzimidazole derivativesFPR1[116]
AG-09/16, AG-09/17, AG-09/20, and AG-09/22 through AG-09/24Benzimidazole derivativesFPR1, FPR2
AG-09/3, AG-09/4, AG-09/73 through AG-09/77, and AG-09/82N-phenylurea derivativesFPR2
AG-09/7, AG-09/92, AG-09/92, AG-09/96, AG-09/101, and AG-09/102Acetohydrazide derivativesFPR2 [low efficacy]
Compound17a/17b/14aSynthetic libraryFPR1, FPR2[124,125]
Compound43Synthetic libraryFPR1, FPR2[79]
Table 7. Non-human, non-microbe-derived FPR (Fpr) ligands.
Table 7. Non-human, non-microbe-derived FPR (Fpr) ligands.
AgonistClassificationReceptorCitation
Scholopendrasin IXCentipede PeptidesFPR2[131]
Scholopendrasin III and VFPR1[127]
RubimetideSpinachFPR2[98]
Piscidin 1 and 3From fishFPR2[130]
Temporin AFrom frogsFPR2[128]
Rana-6FPR2

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top