New Selective Peptidyl Di(chlorophenyl) Phosphonate Esters for Visualizing and Blocking Neutrophil Proteinase 3 in Human Diseases

Guarino, Carla; Łęgowska, Anna; Epinette, Christophe; Kellenberger, Christine; Dallet‐Choisy, Sandrine; Sieńczyk, Marcin; Gabant, Guillaume; Cadène, Martine; Zoidakis, Jérôme; Vlahou, Antonia; Wysocka, Magdalena; Marchand-Adam, S.; Jenne, Dieter E.; Lesner, Adam; Gauthier, Francis; Korkmaz, Brice

doi:10.1074/jbc.m114.591339

Cited by 38 publications

(54 citation statements)

References 51 publications

(69 reference statements)

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“…Extravidin-peroxidase Detection of Active PR3-Active PR3 in PLB-985, HL-60, and neutrophil lysates was detected using selective PR3 activity-based probe Bt-[PEG] 66 -PYDA P (O-C 6 H 4 -4-Cl) 2 (31). The volumes of lysates were adjusted so that the final concentration of PR3 was 20 nM and incubated with Bt-[PEG] 66 -PYDA P (O-C 6 H 4 -4-Cl) 2 (250 nM final) for 30 min at 37°C in PBS.…”

Section: Measurements Of Protease Activities In Cell Lysates and Lungmentioning

confidence: 99%

Neutrophilic Cathepsin C Is Maturated by a Multistep Proteolytic Process and Secreted by Activated Cells during Inflammatory Lung Diseases

Hamon

Łęgowska

Hervé

et al. 2016

Journal of Biological Chemistry

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The cysteine protease cathepsin C (CatC) activates granuleassociated proinflammatory serine proteases in hematopoietic precursor cells. Its early inhibition in the bone marrow is regarded as a new therapeutic strategy for treating proteolysisdriven chronic inflammatory diseases, but its complete inhibition is elusive in vivo. Controlling the activity of CatC may be achieved by directly inhibiting its activity with a specific inhibitor or/and by preventing its maturation. We have investigated immunochemically and kinetically the occurrence of CatC and its proform in human hematopoietic precursor cells and in differentiated mature immune cells in lung secretions. The maturation of proCatC obeys a multistep mechanism that can be entirely managed by CatS in neutrophilic precursor cells. CatS inhibition by a cell-permeable inhibitor abrogated the release of the heavy and light chains from proCatC and blocked ϳ80% of CatC activity. Under these conditions the activity of neutrophil serine proteases, however, was not abolished in precursor cell cultures. In patients with neutrophilic lung inflammation, mature CatC is found in large amounts in sputa. It is secreted by activated neutrophils as confirmed through lipopolysaccharide administration in a nonhuman primate model. CatS inhibitors currently in clinical trials are expected to decrease the activity of neutrophilic CatC without affecting those of elastase-like serine proteases.

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Section: Measurements Of Protease Activities In Cell Lysates and Lungmentioning

confidence: 99%

Neutrophilic Cathepsin C Is Maturated by a Multistep Proteolytic Process and Secreted by Activated Cells during Inflammatory Lung Diseases

Hamon

Łęgowska

Hervé

et al. 2016

Journal of Biological Chemistry

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“…In addition, there is a charged arginyl residue at position 217 in HNE in the vicinity of S4, whereas it is an Ile in PR3. Our recent study using single-residue mutant PR3 with Arg at position 217 (PR3I217R) revealed that Ile217 in the vicinity of the S4 pocket greatly influences the substrate specificity of PR3 (Guarino et al, 2014).…”

Section: B Substrate Binding Sitesmentioning

confidence: 99%

“…This compound is a highly useful tool to identify soluble active PR3 in biologic samples, such as inflammatory lung secretions and the urine of patients with bladder cancer. The same compound can also be taken to visualize intracellular PR3 and PR3 m on activated neutrophils (Guarino et al, 2014).…”

mentioning

confidence: 99%

“…We recently designed and synthesized new phosphonate inhibitors based on structural differences between PR3 and HNE (Guarino et al, 2014). The combination of a prolyl residue at P4 and an aspartyl residue at P2 yielded the first selective chlorodiphenyl phosphonate inhibitors of PR3 with the structure Acpeptidyl P (O-C 6 H 4 -4-Cl) 2 .…”

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confidence: 99%

“…The replacement of the N-terminal acetyl group by hexanoic acid, 6-amino-hexanoic acid, or biotin resulted in a significant improvement in the k obs/ [I] value (Table 4). The N-terminally biotinylated inhibitor containing polyethylene glycol (PEG) as a spacer Bt- [PEG] 66 -Pro-Tyr-Asp-Ala P (O-C 6 H 4 -4-Cl) 2 acts as activity-based probe and can be used to visualize cellular or extracellular PR3 in native conditions using labeled extravidin/avidin (Guarino et al, 2014) (Fig. 8B).…”

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confidence: 99%

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Inhibitors and Antibody Fragments as Potential Anti-Inflammatory Therapeutics Targeting Neutrophil Proteinase 3 in Human Disease

Korkmaz¹,

Lesner²,

Guarino³

et al. 2016

Pharmacol Rev

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Proteinase 3 (PR3) has received great scientific attention after its identification as the essential antigenic target of antineutrophil cytoplasm antibodies in Wegener's granulomatosis (now called granulomatosis with polyangiitis). Despite many structural and functional similarities between neutrophil elastase (NE) and PR3 during biosynthesis, storage, and extracellular release, unique properties and pathobiological functions have emerged from detailed studies in recent years. The development of highly sensitive substrates and inhibitors of human PR3 and the creation of PR3-selective single knockout mice led to the identification of nonredundant roles of PR3 in cell death induction via procaspase-3 activation in cell cultures and in mouse models. According to a study in knockout mice, PR3 shortens the lifespan of infiltrating neutrophils in tissues and accelerates the clearance of aged neutrophils in mice. Membrane exposure of active human PR3 on apoptotic neutrophils reprograms the response of macrophages to phagocytosed neutrophils, triggers secretion of proinflammatory cytokines, and undermines immune silencing and tissue regeneration. PR3-induced disruption of the anti-inflammatory effect of efferocytosis may be relevant for not only granulomatosis with polyangiitis but also for other autoimmune diseases with high neutrophil turnover. Inhibition of membrane-bound PR3 by endogenous inhibitors such as the alpha-1-protease inhibitor is comparatively weaker than that of NE, suggesting that the adverse effects of unopposed PR3 activity resurface earlier than those of NE in individuals with alpha-1-protease inhibitor deficiency. Effective coverage of PR3 by anti-inflammatory tools and simultaneous inhibition of both PR3 and NE should be most promising in the future

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Phosphonic Analogs of Alanine as Acylpeptide Hydrolase Inhibitors

Sieńczyk

Walczak

Chryplewicz

et al. 2021

Chemistry & Biodiversity

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Acylpeptide hydrolase is a serine protease, which, together with prolyl oligopeptidase, dipeptidyl peptidase IV and oligopeptidase B, belongs to the prolyl oligopeptidase family. Its primary function is associated with the removal of N‐acetylated amino acid residues from proteins and peptides. Although the N‐acylation occurs in 50–90 % of eukaryotic proteins, the precise functions of this modification remains unclear. Recent findings have indicated that acylpeptide hydrolase participates in various events including oxidized proteins degradation, amyloid β‐peptide cleavage, and response to DNA damage. Considering the protein degradation cycle cross‐talk between acylpeptide hydrolase and proteasome, inhibition of the first enzyme resulted in down‐regulation of the ubiquitin‐proteasome system and induction of cancer cell apoptosis. Acylpeptide hydrolase has been proposed as an interesting target for the development of new potential anticancer agents. Here, we present the synthesis of simple derivatives of (1‐aminoethyl)phosphonic acid diaryl esters, phosphonic analogs of alanine diversified at the N‐terminus and ester rings, as inhibitors of acylpeptide hydrolase and discuss the ability of the title compounds to induce apoptosis of U937 and MV‐4‐11 tumor cell lines.

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New Selective Peptidyl Di(chlorophenyl) Phosphonate Esters for Visualizing and Blocking Neutrophil Proteinase 3 in Human Diseases

Cited by 38 publications

References 51 publications

Neutrophilic Cathepsin C Is Maturated by a Multistep Proteolytic Process and Secreted by Activated Cells during Inflammatory Lung Diseases

Neutrophilic Cathepsin C Is Maturated by a Multistep Proteolytic Process and Secreted by Activated Cells during Inflammatory Lung Diseases

Inhibitors and Antibody Fragments as Potential Anti-Inflammatory Therapeutics Targeting Neutrophil Proteinase 3 in Human Disease

Phosphonic Analogs of Alanine as Acylpeptide Hydrolase Inhibitors

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