Structure–activity relationship of for-l-Met l-Leu-l-Phe-OMe analogues in human neutrophils

Cavicchioni, Giorgio; Fraulini, Anna; Falzarano, Sofia; Spisani, Susanna

doi:10.1016/j.bioorg.2006.07.001

Cited by 8 publications

(5 citation statements)

References 69 publications

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“…To explore whether inflammatory stimuli lead to histone H3 deimination, we selected a set of treatments that activate or cause degranulation of neutrophils. Each of the selected stimuli ligates different cellular receptors (23)(24)(25)(26)(27), yet leads to elevation of intracellular calcium. Because calcium is required for PAD4 activity, we considered these stimuli as likely candidates for the physiological induction of histone deimination.…”

Section: Stimuli That Induce Histone H3 Deimination In Hl-60 Cellsmentioning

confidence: 99%

Histone Deimination As a Response to Inflammatory Stimuli in Neutrophils

Neeli

Khan

Radic

2008

The Journal of Immunology

496

524

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Posttranslational modifications, such as the deimination of arginine to citrulline by peptidyl arginine deiminase (PAD4), change protein structure and function. For autoantigens, covalent modifications represent a mechanism to sidestep tolerance and stimulate autoimmunity. To examine conditions leading to histone deimination in neutrophils, we used Abs that detect citrullines in the N terminus of histone H3. Deimination was investigated in human neutrophils and HL-60 cells differentiated into granulocytes. We observed rapid and robust H3 deimination in HL-60 cells exposed to LPS, TNF, lipoteichoic acid, f-MLP, or hydrogen peroxide, which are stimuli that activate neutrophils. Importantly, we also observed H3 deimination in human neutrophils exposed to these stimuli. Citrullinated histones were identified as components of extracellular chromatin traps (NETs) produced by degranulating neutrophils. In contrast, apoptosis proceeded without detectable H3 deimination in HL-60 cells exposed to staurosporine or camptothecin. We conclude that histone deimination in neutrophils is induced in response to inflammatory stimuli and not by treatments that induce apoptosis. Our results further suggest that deiminated histone H3, a covalently modified form of a prominent nuclear autoantigen, is released to the extracellular space as part of the neutrophil response to infections. The possible association of a modified autoantigen with microbial components could, in predisposed individuals, increase the risk of autoimmunity.

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Section: Stimuli That Induce Histone H3 Deimination In Hl-60 Cellsmentioning

confidence: 99%

Histone Deimination As a Response to Inflammatory Stimuli in Neutrophils

Neeli

Khan

Radic

2008

The Journal of Immunology

496

524

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“…The number of novel synthetic peptide FPR ligands continues to increase, and there are a couple of excellent reviews in the past few years summarizing these molecules [11, 43, 58, 70-73]. However, peptides are difficult to make and administer as therapeutic agents, making small-molecule chemical compounds a better choice for future clinical development.…”

Section: Therapeutic Efficacy Of Fpr Ligandsmentioning

confidence: 99%

Development of Small Molecule Non-peptide Formyl Peptide Receptor (FPR) Ligands and Molecular Modeling of Their Recognition

Schepetkin¹,

Khlebnikov²,

Giovannoni³

et al. 2014

CMC

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Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) expressed on a variety of cell types. These receptors play an important role in the regulation of inflammatory reactions and sensing cellular damage. They have also been implicated in the pathogenesis of various diseases, including neurodegenerative diseases, cataract formation, and atherogenesis. Thus, FPR ligands, both agonists and antagonists, may represent novel therapeutics for modulating host defense and innate immunity. A variety of molecules have been identified as receptor subtype-selective and mixed FPR agonists with potential therapeutic value during last decade. This review describes our efforts along with recent advances in the identification, optimization, biological evaluation, and structure-activity relationship (SAR) analysis of small molecule non-peptide FPR agonists and antagonists, including chiral molecules. Questions regarding the interaction at the molecular level of benzimidazoles, pyrazolones, pyridazin-3(2H)-ones, N-phenylureas and other derivatives with FPR1 and FPR2 are discussed. Application of computational models for virtual screening and design of FPR ligands is also considered.

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“…Likewise, Bü rli et al (2006) identified potent and specific FPR2 agonists with a 1-(3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-3-phenylurea scaffold. Because aromatic amino acids (Trp, Phe, and Tyr) of peptide FPR1/FPR2 agonists have also been shown to be important moieties for ligand-receptor interactions (Bae et al, 2003b(Bae et al, , 2004Cavicchioni et al, 2006;Wan et al, 2007;Movitz et al, 2010), we selected Trp-and Phe-based N-phenylurea derivatives and related analogs for further screening. These 97 compounds included 7 Trpbased, 49 Phe-based, and 41 other nonpeptoid derivatives (see Tables 2-5 and Supplemental Table S1 for structural details).…”

Section: Identification Of Fpr Agonists By Screening Ofmentioning

confidence: 99%

Gastrin-Releasing Peptide/Neuromedin B Receptor Antagonists PD176252, PD168368, and Related Analogs Are Potent Agonists of Human Formyl-Peptide Receptors

et al. 2010

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N-Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) involved in host defense and sensing cellular dysfunction. Thus, FPRs represent important therapeutic targets. In the present studies, we screened 32 ligands (agonists and antagonists) of unrelated GPCRs for their ability to induce intracellular Ca 2ϩ mobilization in human neutrophils and HL-60 cells transfected with human FPR1, FPR2, or FPR3. Screening of these compounds demonstrated that antagonists of gastrin-releasing peptide/neuromedin B receptors ( -(4-nitrophenyl) Phe-based PD176252/PD168368 analogs and 41 related nonpeptide/nonpeptoid analogs revealed 22 additional FPR agonists. Most were potent mixed FPR1/FPR2/FPR3 agonists with nanomolar EC 50 values for FPR2, making them among the most potent nonpeptide FPR2 agonists reported to date. In addition, these agonists were also potent chemoattractants for murine and human neutrophils and activated reactive oxygen species production in human neutrophils. Molecular modeling of the selected agonists using field point methods allowed us to modify our previously reported pharmacophore model for the FPR2 ligand binding site. This model suggests the existence of three hydrophobic/aromatic subpockets and several binding poses of FPR2 agonists in the transmembrane region of this receptor. These studies demonstrate that FPR agonists could include ligands of unrelated GPCR and that analysis of such compounds can enhance our understanding of pharmacological effects of these ligands.

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Structure–activity relationship of for-l-Met l-Leu-l-Phe-OMe analogues in human neutrophils

Cited by 8 publications

References 69 publications

Histone Deimination As a Response to Inflammatory Stimuli in Neutrophils

Histone Deimination As a Response to Inflammatory Stimuli in Neutrophils

Development of Small Molecule Non-peptide Formyl Peptide Receptor (FPR) Ligands and Molecular Modeling of Their Recognition

Gastrin-Releasing Peptide/Neuromedin B Receptor Antagonists PD176252, PD168368, and Related Analogs Are Potent Agonists of Human Formyl-Peptide Receptors

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