Adenosine A2A receptor as a drug target for treatment of sepsis

Сивак, К. В.; Васин, А. В.; Егоров, Владимир В.; Tsevtkov, V. B.; Kuz’mich, N. N.; Savina, V A; Киселев, О. И.

doi:10.1134/s0026893316020230

Cited by 17 publications

(17 citation statements)

References 44 publications

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“…The A 2A AR is a GPCR that plays a key role in the immune and neurological systems . In the immune system, the receptor is anti‐inflammatory, and activation of the A 2A AR leads to an inhibition of pro‐inflammatory cytokines and a secretion of anti‐inflammatory cytokines . In the neurological disorders, such as Parkinson's disease, A 2A AR activation acts counter to the D 2 dopamine receptor .…”

Section: Resultsmentioning

confidence: 99%

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Mapping the allosteric sites of the A_2A adenosine receptor

2017

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The A adenosine receptor (A AR) is a G protein-coupled receptor that is pharmacologically targeted for the treatment of inflammation, sepsis, cancer, neurodegeneration, and Parkinson's disease. Recently, we applied long-timescale molecular dynamics simulations on two ligand-free receptor conformations, starting from the agonist-bound (PDB ID: 3QAK) and antagonist-bound (PDB ID: 3EML) X-ray structures. This analysis revealed four distinct conformers of the A AR: the active, intermediate 1, intermediate 2, and inactive. In this study, we apply the fragment-based mapping algorithm, FTMap, on these receptor conformations to uncover five non-orthosteric sites on the A AR. Two sites that are identified in the active conformation are located in the intracellular region of the transmembrane helices (TM) 3/TM4 and the G protein-binding site in the intracellular region between TM2/TM3/TM6/TM7. Three sites are identified in the intermediate 1 and intermediate 2 conformations, annexing a site in the lipid interface of TM5/TM6. Five sites are identified in the inactive conformation, comprising a site in the intracellular region of TM1/TM7 and in the extracellular region of TM3/TM4 of the A AR. We postulate that these sites on the A AR be screened for allosteric modulators for the treatment of inflammatory and neurological diseases.

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Section: Resultsmentioning

confidence: 99%

“…In leukocytes, the activation of PKA by the A 2A AR produces anti‐inflammatory effects . Furthermore, a knockout of the A 2A AR in mice causes an accumulation of pro‐inflammatory cytokines and leads to tissue damage .…”

Section: Introductionmentioning

confidence: 99%

Mapping the allosteric sites of the A_2A adenosine receptor

2017

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“…Adenosine receptors are G protein coupled receptors and are consist of four subtypes: A1, A2A, A2B, and A3 7 . Adenosine A2A receptor are widely distributed in brain tissues 8 .…”

Section: Introductionmentioning

confidence: 99%

“…6 Adenosine receptors are G protein coupled receptors and are consist of four subtypes: A1, A2A, A2B, and A3. 7 Adenosine A2A receptor are widely distributed in brain tissues. 8 Accumulating evidences have revealed that A2A receptors respond to the adenosine stimulation and thus modulate multiple physiological and pathophysiological processes including memory formation, emotionstate alteration, inflammatory reaction, immune regulation, braininjury repair, and aging process.…”

Section: Introductionmentioning

confidence: 99%

Adenosine A2A receptor activation reduces brain metastasis via SDF‐1/CXCR4 axis and protecting blood‐brain barrier

Chen

Zhou

et al. 2020

Molecular Carcinogenesis

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Brain metastasis is a leading cause of death worldwide, but the mechanism involved remains unclear. Stromal cell‐derived factor‐1 (SDF‐1)/C‐X‐C motif chemokine receptor 4 (CXCR4) signaling has been reported to induce the directed metastasis of cancers, and adenosine A2A receptor activation suppresses the SDF‐1/CXCR4 interaction. However, whether A2A receptor activation implicates the SDF‐1/CXCR4 signaling pathway and thus modulates brain metastasis remains unclear. In this study, Western blot was performed to evaluate the protein levels. Cell invasion and migration assays were used to estimate the metastasis ability of PC‐9 cells. The viability of cells was demonstrated by lactate dehydrogenase and cell proliferation assays. And the findings in vitro were further identified in nude mice. Notably, adenosine A2A receptor activation inhibited the proliferation and viability of PC‐9 cells and thus suppressed the brain metastasis. A2A receptor stimulation protected the function of blood‐brain barrier (BBB). The suppression of brain metastasis and the protection of BBB by A2A receptor relied on SDF‐1/CXCR4 signaling, and treatment using A2A receptor agonist and CXCR4 antagonist protected the nude mice from malignancy metastasis in vivo. Adenosine A2A receptor activation suppressed the brain metastasis by implicating the SDF‐1/CXCR4 axis and protecting the BBB.

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“…More potent and selective A 2A AR agonist ATL-313 13b and other A 2A AR agonists are being considered for treatment of inflammatory pain and sepsis. 3,22,23 The potential of using A 2A AR antagonists, for example, 30-35, to boost the immunotherapy of cancer is based on blocking the effects of elevated adenosine levels in the tumor microenvironment that suppress the immune response, and many pharma companies are actively pursuing this concept. 24 Nonnucleoside A 2B AR agonist BAY 60-6583 14 has been noted to act as partial agonist or even antagonist at that receptor in different models.…”

Section: Introductionmentioning

confidence: 99%

Ocular Purine Receptors as Drug Targets in the Eye

Civan

2016

Journal of Ocular Pharmacology and Therapeutics

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Agonists and antagonists of various subtypes of G protein coupled adenosine receptors (ARs), P2Y receptors (P2YRs), and ATP-gated P2X receptor ion channels (P2XRs) are under consideration as agents for the treatment of ocular diseases, including glaucoma and dry eye. Numerous nucleoside and nonnucleoside modulators of the receptors are available as research tools and potential therapeutic molecules. Three of the 4 subtypes of ARs have been exploited with clinical candidate molecules for treatment of the eye: A 1 , A 2A , and A 3 . An A 1 AR agonist is in clinical trials for glaucoma, A 2A AR reduces neuroinflammation, A 3 AR protects retinal ganglion cells from apoptosis, and both A 3 AR agonists and antagonists had been reported to lower intraocular pressure (IOP). Extracellular concentrations of endogenous nucleotides, including dinucleoside polyphosphates, are increased in pathological states, activating P2Y and P2XRs throughout the eye. P2YR agonists, including P2Y 2 and P2Y 6 , lower IOP. Antagonists of the P2X7R prevent the ATP-induced neuronal apoptosis in the retina. Thus, modulators of the purinome in the eye might be a source of new therapies for ocular diseases.

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Adenosine A2A receptor as a drug target for treatment of sepsis

Cited by 17 publications

References 44 publications

Mapping the allosteric sites of the A_2A adenosine receptor

Mapping the allosteric sites of the A_2A adenosine receptor

Adenosine A2A receptor activation reduces brain metastasis via SDF‐1/CXCR4 axis and protecting blood‐brain barrier

Ocular Purine Receptors as Drug Targets in the Eye

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Adenosine A2A receptor as a drug target for treatment of sepsis

Cited by 17 publications

References 44 publications

Mapping the allosteric sites of the A2A adenosine receptor

Mapping the allosteric sites of the A2A adenosine receptor

Adenosine A2A receptor activation reduces brain metastasis via SDF‐1/CXCR4 axis and protecting blood‐brain barrier

Ocular Purine Receptors as Drug Targets in the Eye

Contact Info

Product

Resources

About

Mapping the allosteric sites of the A_2A adenosine receptor

Mapping the allosteric sites of the A_2A adenosine receptor