Pyroglutamide-Based P2X7 Receptor Antagonists Targeting Inflammatory Bowel Disease

Homerin, Germain; Jawhara, Samir; Dezitter, Xavier; Baudelet, Davy; Dufrénoy, Philippe; Rigo, Benoı̂t; Millet, Régis; Furman, Christophe; Ragé, Guillaume; Lipka, Emmanuelle; Farce, Amaury; Renault, Nicolas; Sendid, Boualem; Charlet, Rogatien; Leroy, Jordan; Phanithavong, Mélodie; Richeval, Camille; Wiart, Jean-François; Allorge, Delphine; Adriouch, Sahil; Vouret‐Craviari, Valérie; Ghinet, Alina

doi:10.1021/acs.jmedchem.9b00584

Cited by 28 publications

(18 citation statements)

References 66 publications

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“…BzATP increased the uptake of TO-PRO-3 in immune cells from both non-tumor and tumor areas ( Figure 2 A-B). This increase was prevented in cells pre-treated with the specific P2RX7 inhibitor, GSK1370319A 35 , indicating that TO-PRO-3 uptake was dependent on the expression of P2RX7. In addition, the macropore activity was delayed in the tumor compartment.…”

Section: Resultsmentioning

confidence: 98%

P2RX7B is a new theranostic marker for lung adenocarcinoma patients

et al. 2020

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Rationale: The characterization of new theranostic biomarkers is crucial to improving the clinical outcome of patients with advanced lung cancer. Here, we aimed at characterizing the P2RX7 receptor, a positive modulator of the anti-tumor immune response, in patients with lung adenocarcinoma. Methods: The expression of P2RX7 and its splice variants was analyzed by RT-qPCR using areas of tumor and non-tumor lung adenocarcinoma (LUAD) tissues on both immune and non-immune cells. The biological activity of P2RX7 was studied by flow cytometry using fluorescent dyes. Bi-molecular fluorescence complementation and confocal microscopy were used to assess the oligomerization of P2RX7. Tumor immune infiltrates were characterized by immunohistochemistry. Results: Fifty-three patients with LUAD were evaluated. P2RX7A, and 3 alternative splice variants were expressed in LUAD tissues and expression was down regulated in tumor versus adjacent non-tumor tissues. The protein retained biological activity only in immune cells. The P2RX7B splice variant was differentially upregulated in immune cells ( P < 0.001) of the tumor and strong evidence of oligomerization of P2RX7A and B was observed in the HEK expression model, which correlated with a default in the activity of P2RX7. Finally, LUAD patients with a high level of P2RX7B had non-inflamed tumors ( P = 0.001). Conclusion: Our findings identified P2RX7B as a new theranostic tool to restore functional P2RX7 activity and open alternative therapeutic opportunities to improve LUAD patient outcome.

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Section: Resultsmentioning

confidence: 98%

P2RX7B is a new theranostic marker for lung adenocarcinoma patients

et al. 2020

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“…To explore the direct interaction of 2354glu or the selective P2X7 receptor inhibitor, A438079, with P2X7 receptors, we investigated the binding modes using a molecular docking study (Gonzaga et al, ; Homerin et al, ) (Figure S5). We found that all parts of 2354glu were in the P2X7 receptor binding pocket consisting of Lys174, Ile109, Thr111, Glu171, Gln143, Lys145, Lys311, and Val173, while part of A438079 was exposed outside the P2X7 receptor binding pocket.…”

Section: Resultsmentioning

confidence: 99%

P2X7 receptor‐targeted regulation by tetrahydroxystilbene glucoside in alcoholic hepatosteatosis: A new strategy towards macrophage–hepatocyte crosstalk

Zhang

Jiang

Cui

et al. 2020

British J Pharmacology

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Background and Purpose:Regulating macrophage-hepatocyte crosstalk through P2X7 receptors has led to new pharmacological strategies to reverse alcoholic hepatosteatosis. We investigated how tetrahydroxystilbene glucoside (2354glu), isolated from Polygonum multiflorum, modulates macrophage-hepatocyte crosstalk during alcoholic hepatosteatosis.Experimental Approach: A model of alcoholic hepatosteatosis was established by giving ethanol intragastrically to C57BL/6 mice. HepG2 cells were incubated in conditioned medium from LPS+ATP-activated THP-1 human macrophages with silenced or overexpressed P2X7 receptors. THP-1 macrophages or mouse peritoneal macrophages were pretreated with 2354glu for 1 hr prior to LPS+ATP stimulation.Western blots, RT-PCR and immunohistochemical analysis were used, along with over-expression and silencing of P2X7 receptors.Key Results: Knockdown or overexpression of P2X7 receptors in THP-1 macrophages affected release of mature IL-1β and, subsequently, modulated lipid metabolism in HepG2 cells via the LKB-AMPK pathway. 2354glu ameliorated alcoholic hepatosteatosis in mice by regulating LKB1-AMPK-SREBP1 pathway and its target genes. Suppression of P2X7 receptor activation by 2354glu inhibited IL-1β release and reduced macrophage and neutrophil infiltration. In macrophages stimulated with LPS+ATP, expression of P2X7 receptors, caspase-1 and NF-κB, release of IL-1β, calcium influx and PI uptake were reduced by 2354glu. SIRT1-LKB1-AMPK-SREBP1 axis-mediated lipid accumulation in HepG2 cells was reduced when they were cultured with conditioned media from LPS+ATP-activated THP-1 macrophages pretreated with 2354glu.Abbreviations: 2345glu, tetrahydroxystilbene glucoside, 2,3,5,4 0 -tetrahydroxy-stilbene-2-O-β-D-glucoside; AMPK, AMP-activated protein kinase; LKB1, liver kinase B1; NLRP3, nucleotidebinding oligomerization domain-like receptor protein 3; SIRT1, sirtuin 1; SREBP1, sterol regulatory element-binding protein 1; TLRs, toll like receptors.

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“…Despite not having effects on the levels of inflammatory biomarkers, oral administration of AZD9056 induced an overall improvement in the disease symptoms (27). Further investigations are therefore needed to develop P2X7R antagonists that effectively interfere with the inflammatory response; in this regard, several compounds have been proposed and these include Pyroglutamide-Based P2X7R Antagonists (28).…”

Section: P2x Receptor Family Members -P2x7mentioning

confidence: 99%

Control of Gut Inflammation by Modulation of Purinergic Signaling

et al. 2020

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Inflammatory bowel disease (IBD) is a serious inflammatory condition of the gastrointestinal tract. Crohn's disease (CD) and ulcerative colitis (UC) are two of the most common IBD manifestations and are both associated with unfettered inflammation, often refractory to conventional immunosuppressive treatment. In both conditions, imbalance between effector and regulatory cell immune responses has been documented and is thought to contribute to disease pathogenesis. Purinergic signaling is a known modulator of systemic and local inflammation and growing evidences point to extracellular ATP/adenosine imbalance as a key determinant factor in IBD-associated immune dysregulation. In vitro and pre-clinical studies suggest a role for both ATP (P2) and adenosine (P1) receptors in dictating onset and severity of the disease. Moreover, our experimental data indicate ENTPD1/CD39 and CD73 ectoenzymes as pivotal modulators of intestinal inflammation, with clear translational importance. Here we will provide an updated overview of the current knowledge on the role of the purinergic signaling in modulating immune responses in IBD. We will also review and discuss the most promising findings supporting the use of purinergic-based therapies to correct immune dysregulation in CD and UC.

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Pyroglutamide-Based P2X7 Receptor Antagonists Targeting Inflammatory Bowel Disease

Cited by 28 publications

References 66 publications

P2RX7B is a new theranostic marker for lung adenocarcinoma patients

P2RX7B is a new theranostic marker for lung adenocarcinoma patients

P2X7 receptor‐targeted regulation by tetrahydroxystilbene glucoside in alcoholic hepatosteatosis: A new strategy towards macrophage–hepatocyte crosstalk

Control of Gut Inflammation by Modulation of Purinergic Signaling

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