3-(1H-indol-3-yl)-2-[3-(4-nitrophenyl)ureido]propanamide enantiomers with human formyl-peptide receptor agonist activity: Molecular modeling of chiral recognition by FPR2

Schepetkin, Igor A.; Kirpotina, Liliya N.; Khlebnikov, Аndrei I.; Leopoldo, Marcello; Lucente, Ermelinda; Lacivita, Enza; Giorgio, Paola De; Quinn, Mark T.

doi:10.1016/j.bcp.2012.11.015

Cited by 27 publications

(53 citation statements)

References 57 publications

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“…Further structural comparisons demonstrate that other known FPR ligands, such as humanin and f-MLF, also display striking similarities with our agonist model (19). Independent support for our concept came from recent work using non-peptide agonists to identify a potential binding motif in FPR2 (44). Moreover, other FPR agonists, such as phenol-soluble modulin peptide toxins (35), amyloid-β (1-42, 45), or urokinase receptor (46), also fit into this scheme.…”

Section: Bacterial Signal Peptides Exhibit a Unique Set Of Structuralsupporting

confidence: 67%

The sensing of bacteria: emerging principles for the detection of signal sequences by formyl peptide receptors

Bufe

Zufall

2016

Biomolecular Concepts

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The ability to detect specific chemical signatures released by bacteria and other microorganisms is a fundamental feature of immune defense against pathogens. There is increasing evidence that chemodetection of such microorganism-associated molecular patterns (MAMPs) occurs at many places in the body including specific sets of chemosensory neurons in the mammalian nose. Formyl peptide receptors (FPRs) are a unique family of G protein-coupled receptors (GPCRs) that can detect the presence of bacteria and function as chemotactic receptors. Here, we highlight the recent discovery of a vast family of natural FPR agonists, the bacterial signal peptides (or signal sequences), thus providing new insight into the molecular mechanisms of bacterial sensing by human and mouse FPRs. Signal peptides in bacteria are formylated, N-terminal protein signatures required for directing the transfer of proteins through the plasma membrane. After their cleavage and release, signal peptides are available for FPR detection and thus provide a previously unrecognized MAMP. With over 170 000 predicted sequences, bacterial signal peptides represent one of the largest families of GPCR ligands and one of the most complex classes of natural activators of the innate immune system. By recognizing a conserved three-dimensional peptide motif, FPRs employ an unusual detection mechanism that combines structural promiscuity with high specificity and sensitivity, thus solving the problem of detecting thousands of distinct sequences yet maintaining selectivity. How signal peptides are released by bacteria and sensed by GPCRs and how these processes shape the responses of other cells and whole organisms represents an important topic for future research.

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Section: Bacterial Signal Peptides Exhibit a Unique Set Of Structuralsupporting

confidence: 67%

The sensing of bacteria: emerging principles for the detection of signal sequences by formyl peptide receptors

Bufe

Zufall

2016

Biomolecular Concepts

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“…3I). Independent support for this concept comes from a recent study using non-peptide agonists to identify a potential binding motif in FPR2 (56). Moreover, other FPR agonists, such as phenol-soluble modulin peptide toxins (15), amyloid-␤(1-42) (8), or PAR (57), may also fit into this scheme.…”

Section: Discussionmentioning

confidence: 84%

Recognition of Bacterial Signal Peptides by Mammalian Formyl Peptide Receptors

Bufe¹,

Schumann²,

Kappl

et al. 2015

Journal of Biological Chemistry

122

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Background:The function of formyl peptide receptors (FPRs) is incompletely understood. Results: We report the identification of bacterial signal peptides as potent activators of mammalian FPRs and innate immune responses and define critical features underlying FPR peptide recognition. Conclusion: These findings identify a molecular signature for FPR activation. Significance: Our results define a novel mechanism for sensing bacteria.

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“…We used a ligand-based approach for molecular modeling known as field point methodology [37, 38], as described previously [39]. The structures of the compounds were pre-optimized by the semi-empirical PM3 method using HyperChem 8.0 software.…”

Section: Methodsmentioning

confidence: 99%

Antagonism of human formyl peptide receptor 1 (FPR1) by chromones and related isoflavones

Schepetkin

Kirpotina

Khlebnikov

et al. 2014

Biochemical Pharmacology

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Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) expressed on a variety of cell types. Because FPRs play an important role in the regulation of inflammatory reactions implicated in disease pathogenesis, FPR antagonists may represent novel therapeutics for modulating innate immunity. Previously, 4H-chromones were reported to be potent and competitive FPR1 antagonists. In the present studies, 96 additional chromone analogs, including related synthetic and natural isoflavones were evaluated for FPR1 antagonist activity. We identified a number of novel competitive FPR1 antagonists that inhibited fMLF-induced intracellular Ca2+ mobilization in FPR1-HL60 cells and effectively competed with WKYMVm-FITC for binding to FPR1 in FPR1-HL60 and FPR1-RBL cells. Compound 10 (6-hexyl-2-methyl-3-(1-methyl-1H-benzimidazol-2-yl)-4-oxo-4H-chromen-7-yl acetate) was found to be the most potent FPR1-specific antagonist, with binding affinity Ki~100 nM. These chromones inhibited Ca2+ flux and chemotaxis in human neutrophils with nanomolar-micromolar IC50 values. In addition, the most potent novel FPR1 antagonists inhibited fMLF-induced phosphorylation of extracellular signal-regulated kinases (ERK1/2) in FPR1-RBL cells. These antagonists were specific for FPR1 and did not inhibit WKYMVM/WKYMVm-induced intracellular Ca2+ mobilization in FPR2-HL60 cells, FPR3-HL60 cells, RBL cells transfected with murine Fpr1, or interleukin 8-induced Ca2+ flux in human neutrophils and RBL cells transfected with CXC chemokine receptor 1 (CXCR1). Moreover, pharmacophore modeling showed that the active chromones had a significantly higher degree of similarity with the pharmacophore template as compared to inactive analogs. Thus, the chromone/isoflavone scaffold represents a relevant backbone for development of novel FPR1 antagonists.

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3-(1H-indol-3-yl)-2-[3-(4-nitrophenyl)ureido]propanamide enantiomers with human formyl-peptide receptor agonist activity: Molecular modeling of chiral recognition by FPR2

Cited by 27 publications

References 57 publications

The sensing of bacteria: emerging principles for the detection of signal sequences by formyl peptide receptors

The sensing of bacteria: emerging principles for the detection of signal sequences by formyl peptide receptors

Recognition of Bacterial Signal Peptides by Mammalian Formyl Peptide Receptors

Antagonism of human formyl peptide receptor 1 (FPR1) by chromones and related isoflavones

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