scholarly journals Aurantiamide-related dipeptide derivatives are formyl peptide receptor 1 antagonists

MedChemComm ◽  
2019 ◽  
Vol 10 (12) ◽  
pp. 2078-2088
Author(s):  
Margherita Mastromarino ◽  
Liliya N. Kirpotina ◽  
Igor A. Schepetkin ◽  
Mark T. Quinn ◽  
Enza Lacivita ◽  
...  
Keyword(s):  
Formyl Peptide Receptor ◽  
Neutrophil Chemotaxis ◽  
Peptide Receptor ◽  
Formyl Peptide

Aurantiamide is a useful scaffold to develop promising FPR1 antagonists capable of inhibiting neutrophil chemotaxis.

The synthetic chemoattractant Trp-Lys-Tyr-Met-Val-DMet activates neutrophils preferentially through the lipoxin A4 receptor

Blood ◽  
2000 ◽  
Vol 95 (5) ◽  
pp. 1810-1818 ◽  
Author(s):  
Claes Dahlgren ◽  
Thierry Christophe ◽  
Francois Boulay ◽  
Phoebus N. Madianos ◽  
Marie J. Rabiet ◽  
...  
Keyword(s):  
Formyl Peptide Receptor ◽  
Neutrophil Chemotaxis ◽  
Lipoxin A4 ◽  
Independent Manner ◽  
Effector Functions ◽  
Peptide Receptor ◽  
Formyl Peptide ◽  
Complement Receptor 3 ◽  
Neutrophil Response ◽  
Cyclosporin H

A D-methionine–containing peptide, Trp-Lys-Tyr-Met-Val-D-Met-NH2 (WKYMVm), featuring a unique receptor specificity was investigated with respect to its ability to activate neutrophil effector functions. The peptide was found to be more potent than the N-formylated peptide N-formyl-Met-Leu-Phe (fMLF) at inducing neutrophil chemotaxis, mobilization of neutrophil complement receptor 3 (CR3), and activation of the neutrophil NADPH-oxidase. The fact that binding of fML[3H]F was inhibited by both fMLF and WKYMVm suggests that N-formyl peptide receptor (FPR) is shared by these peptides. However, the neutrophil response induced by the WKYMVm peptide was insensitive to the fMLF antagonists, cyclosporin H, and Boc-FLFLF that specifically block the function of the FPR. These results suggest that even though WKYMVm may bind FPR the cells are activated preferentially through a receptor distinct from the FPR. Using transfected HL-60 cells expressing either the FPR or its neutrophil homologue FPRL1, also referred to as LXA4R because it has been shown to bind lipoxin A4, we show that WKYMVm is about 300-fold more active at mobilizing intracellular calcium through FPRL1 than through FPR. The WKYMVm activates FPRL1-expressing cells in a cyclosporin H-independent manner with an EC50 of around 75 pmol/L, whereas it activates FPR-expressing cells with an EC50 of around 25 nmol/L. The observation that exudated cells are primed in their response to WKYMVm suggests that FPRL1/LXA4R like FPR is stored in mobilizable organelles.

scholarly journals Innate Immunomodulatory Activity of Cedrol, a Component of Essential Oils Isolated from Juniperus Species

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7644
Author(s):  
Gulmira Özek ◽  
Igor A. Schepetkin ◽  
Moldir Yermagambetova ◽  
Temel Özek ◽  
Liliya N. Kirpotina ◽  
...  
Keyword(s):  
Essential Oils ◽  
Compositional Analysis ◽  
Formyl Peptide Receptor ◽  
Human Neutrophils ◽  
Immunomodulatory Activity ◽  
Neutrophil Chemotaxis ◽  
Pharmacophore Mapping ◽  
Peptide Receptor ◽  
Formyl Peptide ◽  
Similarities And Differences

Little is known about the immunomodulatory activity of essential oils isolated from Juniperus species. Thus, we isolated essential oils from the cones and leaves of eight juniper species found in Montana and in Kazakhstan, including J. horizontalis, J. scopolorum, J. communis, J. seravschanica, J. sabina, J. pseudosabina, J. pseudosabina subsp. turkestanica, and J. sibirica. We report here the chemical composition and innate immunomodulatory activity of these essential oils. Compositional analysis of the 16 samples of Juniper essential oils revealed similarities and differences between our analyses and those previously reported for essential oils from this species. Our studies represent the first analysis of essential oils isolated from the cones of four of these Juniper species. Several essential oil samples contained high levels of cedrol, which was fairly unique to three Juniper species from Kazakhstan. We found that these essential oils and pure (+)-cedrol induced intracellular Ca2+ mobilization in human neutrophils. Furthermore, pretreatment of human neutrophils and N-formyl peptide receptor 1 and 2 (FPR1 and FPR2) transfected HL60 cells with these essential oils or (+)-cedrol inhibited agonist-induced Ca2+ mobilization, suggesting these responses were desensitized by this pretreatment. In support of this conclusion, pretreatment with essential oils from J. seravschanica cones (containing 16.8% cedrol) or pure (+)-cedrol inhibited human neutrophil chemotaxis to N-formyl peptide. Finally, reverse pharmacophore mapping predicted several potential kinase targets for cedrol. Thus, our studies have identified cedrol as a novel neutrophil agonist that can desensitize cells to subsequent stimulation by N-formyl peptide.

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