Agonists, Antagonists, and Modulators of P2X7 Receptors

2’3’-cGAMP is a key molecule in the cGAS-STING pathway. This cyclic dinucleotide is produced by the cytosolic DNA sensor cGAS in response to the presence of aberrant dsDNA in the cytoplasm which is associated with microbial invasion or cellular damage. 2’3’-cGAMP acts as a second messenger and activates STING, the central hub of DNA sensing, to induce type-I interferons and pro-inflammatory cytokines necessary for responses against infection, cancer or cellular stress. Classically, detection of pathogens or danger by pattern recognition receptors (PRR) was thought to signal and induce the production of interferon and pro-inflammatory cytokines in the cell where sensing occurred. These interferon and cytokines then signal in both an autocrine and paracrine manner to induce responses in neighboring cells. Deviating from this dogma, recent studies have identified multiple mechanisms by which 2’3’-cGAMP can travel to neighboring cells where it activates STING independent of DNA sensing by cGAS. This observation is of great importance, as the cGAS-STING pathway is involved in immune responses against microbial invaders and cancer while its dysregulation drives the pathology of a wide range of inflammatory diseases to which antagonists have been elusive. In this review, we describe the fast-paced discoveries of the mechanisms by which 2’3’-cGAMP can be transported. We further highlight the diseases where they are important and detail how this change in perspective can be applied to vaccine design, cancer immunotherapies and treatment of cGAS-STING associated disease.

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“…Ψ reviewed by Salameh and Dhein ( 23 ). λ reviewed by Müller and Namasivayam ( 24 ). ω reviewed by Cole ( 25 ).…”

Section: Mechanisms Of Cgamp Inter-cellular Signalingmentioning

confidence: 99%

“…Likely as a result of membrane disintegration, cGAMP and ATP are released into the tumor microenvironment. ATP activates P2X7 pore expressed by TAMs allowing cGAMP to passively move across the plasma membrane and drive type I IFN production through STING ( 1 , 3 – 6 , 24 , 42 – 63 ).…”

Section: Mechanisms Of Cgamp Inter-cellular Signalingmentioning

confidence: 99%

cGAMP the travelling messenger

Blest

Chauveau

2023

Front. Immunol.

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“…However, basal stimulation of the receptor with subthreshold concentrations of the agonist, such as those in the TME, was also associated with trophic properties [ 1 , 22 ]. The functional P2X7 receptor is a homotrimer [ 23 ] formed by subunits of 595 amino acids whose tridimensional structure was recently identified and exploited for identifying and designing new receptor ligands [ 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. The P2X7 subunit is formed by a short N terminal domain, two transmembrane regions, a large extracellular domain with ligand binding sites, and a long intracellular C terminal tail.…”

Section: The P2x7 Receptor and Its Splice Variantsmentioning

confidence: 99%

The P2X7 Receptor in Oncogenesis and Metastatic Dissemination: New Insights on Vesicular Release and Adenosinergic Crosstalk

Adinolfi,

De Marchi,

Grignolo

et al. 2023

IJMS

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The tumor niche is an environment rich in extracellular ATP (eATP) where purinergic receptors have essential roles in different cell subtypes, including cancer, immune, and stromal cells. Here, we give an overview of recent discoveries regarding the role of probably the best-characterized purinergic receptor in the tumor microenvironment: P2X7. We cover the activities of the P2X7 receptor and its human splice variants in solid and liquid cancer proliferation, dissemination, and crosstalk with immune and endothelial cells. Particular attention is paid to the P2X7-dependent release of microvesicles and exosomes, their content, including ATP and miRNAs, and, in general, P2X7-activated mechanisms favoring metastatic spread and niche conditioning. Moreover, the emerging role of P2X7 in influencing the adenosinergic axis, formed by the ectonucleotidases CD39 and CD73 and the adenosine receptor A2A in cancer, is analyzed. Finally, we cover how antitumor therapy responses can be influenced by or can change P2X7 expression and function. This converging evidence suggests that P2X7 is an attractive therapeutic target for oncological conditions.

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“…P2X4 receptors are involved in tactile allodynia following nerve damage ( Tsuda et al, 2003 ), and P2X7 receptors are thought to modulate inflammatory responses in conditions including arthritis, Crohn’s disease and age-related macular degeneration, as well as being involved in cancer progression and mood disorders ( Ren and Illes, 2022 ). Due to their involvement in inflammatory disease, P2X receptors are important drug targets ( Dane et al, 2022 ) and many P2X4 and P2X7 antagonists have been discovered and developed, largely using high throughput screening approaches ( Hernandez-Olmos et al, 2012 ; Ase et al, 2015 ; Müller and Namasivayam, 2022 ), but also by structure-based screening ( Caseley et al, 2016 ; Zhao et al, 2021 ). The discovery of novel P2X4 receptor antagonists has been more of a challenge than for P2X7, and this may be because many antagonists (including BX430 and 5-BDBD for P2X4 ( Fischer et al, 2004 ; Ase et al, 2015 ), and A740003, A804598, AZ10606120, GW791343, JNJ47965567, A438079 and AZ11645373 for P2X7 ( Honore et al, 2006 ; Karasawa and Kawate, 2016 ; Allsopp et al, 2018 ; Bin Dayel et al, 2019 )) bind to an allosteric pocket in the extracellular domain, which is smaller in P2X4 than P2X7 ( Karasawa and Kawate, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel P2X7 antagonist using structure-based virtual screening

et al. 2023

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P2X4 and P2X7 receptors are ATP-gated ion channels, which play important roles in neuropathic and inflammatory pain, and as such they are important drug targets in diseases of inflammatory origin. While several compounds targeting P2X4 and P2X7 receptors have been developed using traditional high-throughput screening approaches, relatively few compounds have been developed using structure-based design. We initially set out to develop compounds targeting human P2X4, by performing virtual screening on the orthosteric (ATP-binding) pocket of a molecular model of human P2X4 based on the crystal structure of the Danio rerio receptor. The screening of a library of approximately 300,000 commercially available drug-like compounds led to the initial selection of 17 compounds; however, none of these compounds displayed a significant antagonist effect at P2X4 in a Fluo-4 ATP-induced calcium influx assay. When the same set of compounds was tested against human P2X7 in an ATP-stimulated Yo-Pro1 dye uptake assay, one compound (an indeno(1,2-b)pyridine derivative; GP-25) reduced the response by greater than 50% when applied at a concentration of 30 µM. GP-25 displayed an IC50 value of 8.7 μM at human P2X7 and 24.4 μM at rat P2X7, and was confirmed to be active using whole-cell patch clamp electrophysiology and not cytotoxic. Schild analysis suggested that mode of action of GP-25 was orthosteric. Screening of a further 16 commercially available analogues of GP-25 led to the discovery of five additional compounds with antagonist activity at human P2X7, enabling us to investigate the structure-activity relationship. Finally, docking of the R- and S-enantiomers of GP-25 into the orthosteric pocket of molecular models of human P2X4 and human P2X7 revealed that, while both enantiomers were able to make multiple interactions between their carboxyl moieties and conserved positively charged amino-acids in human P2X7, only the S-enantiomer of GP-25 was able to do this in human P2X4, potentially explaining the lack of activity of GP-25 at this receptor.

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Agonists, Antagonists, and Modulators of P2X7 Receptors

Cited by 8 publications

References 74 publications

cGAMP the travelling messenger

cGAMP the travelling messenger

The P2X7 Receptor in Oncogenesis and Metastatic Dissemination: New Insights on Vesicular Release and Adenosinergic Crosstalk

Identification of a novel P2X7 antagonist using structure-based virtual screening

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