Design, Synthesis and Characterization of fMLF‐Mimicking AApeptides

Hu, Yucong; Cheng, Ni; Wu, Haifan; Kang, Samuel; Ye, Richard D.; Cai, Jianfeng

doi:10.1002/cbic.201402396

Cited by 8 publications

(11 citation statements)

References 38 publications

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“…This peptide becomes 1000-fold more potent when the first Met is N -formylated, consistent with the preferential recognition of fMet-containing peptides by FPR1. In a recent study [ 141 ], a series of AApeptides, a class of peptidomimetics based on N -acylated- N -aminoethyl amino acid residues, were designed and synthesized to mimic the structure and function of the prototypic tripeptide fMLF, the reference agonist of FPR1. Three of these fMLF-mimicking AApeptides were found effective in activating FPR-expressing cells in calcium mobilization assay, albeit at concentrations above 10 µM.…”

Section: Agonists For the Formyl Peptide Receptorsmentioning

confidence: 99%

The Formyl Peptide Receptors: Diversity of Ligands and Mechanism for Recognition

Ye²

2017

Molecules

219

216

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The formyl peptide receptors (FPRs) are G protein-coupled receptors that transduce chemotactic signals in phagocytes and mediate host-defense as well as inflammatory responses including cell adhesion, directed migration, granule release and superoxide production. In recent years, the cellular distribution and biological functions of FPRs have expanded to include additional roles in homeostasis of organ functions and modulation of inflammation. In a prototype, FPRs recognize peptides containing N-formylated methionine such as those produced in bacteria and mitochondria, thereby serving as pattern recognition receptors. The repertoire of FPR ligands, however, has expanded rapidly to include not only N-formyl peptides from microbes but also non-formyl peptides of microbial and host origins, synthetic small molecules and an eicosanoid. How these chemically diverse ligands are recognized by the three human FPRs (FPR1, FPR2 and FPR3) and their murine equivalents is largely unclear. In the absence of crystal structures for the FPRs, site-directed mutagenesis, computer-aided ligand docking and structural simulation have led to the identification of amino acids within FPR1 and FPR2 that interact with several formyl peptides. This review article summarizes the progress made in the understanding of FPR ligand diversity as well as ligand recognition mechanisms used by these receptors.

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Section: Agonists For the Formyl Peptide Receptorsmentioning

confidence: 99%

The Formyl Peptide Receptors: Diversity of Ligands and Mechanism for Recognition

Ye²

2017

Molecules

219

216

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“…Thus, a ten-residue γ-AApeptide mimic of Tat peptide (GRKKRRQRRRPQ) was able to bind to HIV TAR RNA and BIV TAR RNA with comparable selectivity and specificity to that of the Tat peptide [ 267 ]. Furthermore, γ-AApeptide mimics of RGD peptides (including 64 Cu-labelled compounds) [ 268 ], and of fMLF [ 269 ] (a selective formyl peptide receptor agonist) have been reported. In addition, γ-AApeptides have been shown to disrupt Aβ aggregation in Alzheimer’s disease [ 270 ], and to have potential applications in biomaterial science [ 271 ].…”

Section: Peptidomimeticsmentioning

confidence: 99%

Advances in Development of Antimicrobial Peptidomimetics as Potential Drugs

2017

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The rapid emergence of multidrug-resistant pathogens has evolved into a global health problem as current treatment options are failing for infections caused by pan-resistant bacteria. Hence, novel antibiotics are in high demand, and for this reason antimicrobial peptides (AMPs) have attracted considerable interest, since they often show broad-spectrum activity, fast killing and high cell selectivity. However, the therapeutic potential of natural AMPs is limited by their short plasma half-life. Antimicrobial peptidomimetics mimic the structure and biological activity of AMPs, but display extended stability in the presence of biological matrices. In the present review, focus is on the developments reported in the last decade with respect to their design, synthesis, antimicrobial activity, cytotoxic side effects as well as their potential applications as anti-infective agents. Specifically, only peptidomimetics with a modular structure of residues connected via amide linkages will be discussed. These comprise the classes of α-peptoids (N-alkylated glycine oligomers), β-peptoids (N-alkylated β-alanine oligomers), β3-peptides, α/β3-peptides, α-peptide/β-peptoid hybrids, α/γ N-acylated N-aminoethylpeptides (AApeptides), and oligoacyllysines (OAKs). Such peptidomimetics are of particular interest due to their potent antimicrobial activity, versatile design, and convenient optimization via assembly by standard solid-phase procedures.

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“…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 Ca 2+ 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.…”

Section: Synthetic Peptides and Non-peptide Small Moleculesmentioning

confidence: 99%

Chemotactic Ligands that Activate G-Protein-Coupled Formylpeptide Receptors

Krepel

Wang

2019

IJMS

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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.

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Design, Synthesis and Characterization of fMLF‐Mimicking AApeptides

Cited by 8 publications

References 38 publications

The Formyl Peptide Receptors: Diversity of Ligands and Mechanism for Recognition

The Formyl Peptide Receptors: Diversity of Ligands and Mechanism for Recognition

Advances in Development of Antimicrobial Peptidomimetics as Potential Drugs

Chemotactic Ligands that Activate G-Protein-Coupled Formylpeptide Receptors

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