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Remdesivir has previously unknown anti-viral immunomodulatory properties through the Adenosine A2A Receptor pathway

ABSTRACT: Remdesivir has previously unknown anti-viral immunomodulatory properties through the Adenosine A2A Receptor pathway

PROVIDER: PRJNA991577 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25147032_1.fastq.gz	Fastqsanger.gz
	SRR25147032_2.fastq.gz	Fastqsanger.gz
	SRR25147033_1.fastq.gz	Fastqsanger.gz
	SRR25147033_2.fastq.gz	Fastqsanger.gz
	SRR25147034_1.fastq.gz	Fastqsanger.gz

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Remdesivir has previously unknown anti-viral immunomodulatory properties through the Adenosine A2A Receptor pathway

Project description:The COVID-19 pandemic has unveiled an urgent need for new anti-virals to control emerging infectious diseases and potential future pandemics. Classic anti-virals are currently designed to directly interfere with pathogens. However, anti-virals are often insufficient to rapidly clear infections in the absence of an effective immune response. Immunotherapy could complement the use of anti-virals, however its application to infectious diseases remains largely unexplored. In this work, we found that the anti-viral drug remdesivir has previously unknown immunomodulatory properties which contribute to its therapeutic effect against SARS-CoV-2. These properties are due to remdesivir metabolite, GS-441524, acting as an Adenosine A2A Receptor antagonist, a function that is distinct from its intrinsic anti-viral activity. Our findings support a new rationale for the design of next-generation anti-viral agents with dual – immunomodulatory and intrinsic - anti-viral properties. These compounds could represent game-changing therapies to control emerging viral diseases and future pandemics.

2024-09-11 | GSE236563 | GEO

Elucidation of remdesivir cytotoxicity pathways through genome-wide CRISPR/Cas9 screening and transcriptomics

Project description:The adenosine analogue remdesivir has emerged as a front-line antiviral treatment for SARS-CoV-2, with preliminary evidence that it reduces the duration and severity of illness. As clinical trials are ongoing, the full side effect profile of remdesivir is not yet known. Prior clinical studies have identified adverse events, and remdesivir has been shown to inhibit mitochondrial RNA polymerase in biochemical experiments, yet little is known about the specific genetic pathways involved in cellular remdesivir metabolism and cytotoxicity. Through genome-wide CRISPR/Cas9 screening (data not provided here) and RNA sequencing, we identify specific genes and pathways implicated in remdesivir metabolism. We show that remdesivir treatment leads to a global repression of mitochondrial respiratory activity. Further, we show that loss of the mitochondrial nucleoside transporter SLC29A3 or the mitochondrial adenylate kinase AK2 provide 10-72-fold mitigation of remdesivir toxicity while conserving its antiviral potency. This work provides candidate gene targets to reduce remdesivir toxicity and provides a proof-of-principle for the use of CRISPR/Cas9 screening to elucidate mechanisms of drug cytotoxicity.

2020-09-08 | GSE154936 | GEO

Gene expression profile in the heart of wild type and Adenosine Receptor A2a over expressing mice

Project description:Adenosine binds to 4 G protein-coupled receptors located on the cardiomyocyte (A1-R, A2a-R, A2b-R and A3-R) and modulates cardiac function during both ischemia and load-induced stress. While the role of adenosine receptor-subtypes has been well defined in the setting of ischemia-reperfusion, far less is known regarding their roles in protecting the heart during other forms of cardiac stress. We characterized the gene expression profiles of heart from A2a-R over-expressing mice subjected to transverse aortic constriction to study the potential of A2a-R activation to protect from pressure-induced heart failure.

2015-03-22 | GSE45423 | GEO

Differential gene expression in activated microglia treated with adenosine A2A antagonists and A3 receptor agonists. A transcriptomics study.

Project description:Microglial activation often accompanies the plastic changes occurring in the brain of patients with neurodegenerative diseases. A2A and A3 adenosine receptors have been proposed as therapeutic targets to combat neurodegeneration. RNAseq was performed using samples isolated from lipopolysaccharide/interferon-γ activated microglia treated with SCH 58261, a selective A2A receptor antagonist and 2-Cl-IB-MECA, a selective A3 receptor agonist.

2023-10-04 | GSE222696 | GEO

Microarray analysis of a multiple myeloma cell line, MM1S, treated with adenosine A2A and Beta-2 Adrenergic Receptor agonists in combination with dexamethasone

Project description:We have used an agnostic approach to identify drug combinations by using combination high throughput screening (cHTS) technology and make the surprising discovery that adenosine A2A and beta-2 adrenergic receptor agonists are highly synergistic, selective and novel agents that enhance glucocorticoid activity in B-cell malignancies. We used the microarray study to understand the synergistic mechanism between dexamethasone and A2A receptor agonist or Beta-2 Adrenergic receptor agonist in a multiple myeloma cell line, MM1S. MM1S cells were treated with CGS-21680 or Salmeterol alone, or in combination with dexamethasone for six hours for RNA extraction and hybridization on Affymetrix microarrays.

2012-03-31 | E-GEOD-30644 | biostudies-arrayexpress

Microarray analysis of a multiple myeloma cell line, MM1S, treated with adenosine A2A and Beta-2 Adrenergic Receptor agonists in combination with dexamethasone

2012-04-01 | GSE30644 | GEO

Adenosine A2A Receptor Null Chondrocyte Transcriptome Resembles that of Human Osteoarthiris Chodnrocytes

Project description:Adenosine A2A Receptor Null Chondrocyte Transcriptome Resembles that of Human Osteoarthiris Chodnrocytes

| PRJNA610223 | ENA

Gene expression of SARS-CoV-2-infected Vero E6 cells with remdesivir treatment

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2021-02-02 | GSE165955 | GEO

Intraarticular injection of liposomal adenosine reduces cartilage damage in established murine and rat models of osteoarthritis

Project description:Osteoarthritis (OA) affects nearly 10% of the population of the United States and other industrialized countries and, at present, short of surgical joint replacement, there is no therapy available that can reverse the progression of the disease OA. Adenosine, acting at its A2A receptor (A2AR), is a critical autocrine factor for maintenance of cartilage homeostasis. Here we report that injection of liposomal suspensions of a selective A2AR agonist, CGS21680, significantly reduced OA cartilage damage in a rat model of established post-traumatic OA (PTOA). Differential expression analysis of mRNA from chondrocytes harvested from knees of rats with PTOA treated with liposomal A2AR agonist revealed downregulation of genes associated with matrix degradation and upregulation of genes associated with cell proliferation as compared to liposomes alone.

2020-09-01 | GSE146813 | GEO

Expression data from mouse bone marrow-derived macrophages (BMDMs)

Project description:To recruit phagocytes, apoptotic cells characteristically release ATP, which functions as a “danger” signal. Here, we found that the culture supernatant of apoptotic cells activated the macrophages to express anti-inflammatory genes such as NR4A and Thbs1. A high level of AMP accumulated in the apoptotic cell supernatant in a Pannexin1-dependent manner. A nucleotidase inhibitor and A2a adenosine receptor antagonist inhibited the apoptotic supernatant-induced gene expression, suggesting AMP was metabolized to adenosine by an ecto-5’-nucleotidase expressed on macrophages, to activate the macrophage A2a adenosine receptor. Intraperitoneal injection of zymosan into AdoR A2a- or Panx1-deficient mice produced high, sustained levels of inflammatory mediators in the peritoneal lavage. These results indicated that AMP from apoptotic cells suppresses inflammation as a “calm down” signal. If apoptotic cells produce “danger” or “anti-danger” signal(s), we rationalized that such signals would activate gene expression in macrophages. To investigate this possibility, we examined the effect of the culture supernatant from apoptotic cells on macrophage gene expression by using microarrays.

2014-06-24 | GSE50883 | GEO

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