About: Enhancing the Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with Modulators of Pyrimidine Metabolism

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About: Enhancing the Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with Modulators of Pyrimidine Metabolism Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : covidontheweb.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
title	Enhancing the Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with Modulators of Pyrimidine Metabolism
Creator	Gupta, Amita Liu, Qi Carette, Jan Smith, Mark Bassik, Michael Fischer, Curt Khosla, Chaitan Okesli-Armlovich, Ayse Qiao, Wenjie Khosla Correspondence, Chaitan
source	Elsevier; Medline; PMC
abstract	Genome-wide analysis of the mode of action of GSK983, a potent antiviral agent, led to the identification of dihydroorotate dehydrogenase as its target along with the discovery that genetic knockdown of pyrimidine salvage sensitized cells to GSK983. Because GSK983 is an ineffective antiviral in the presence of physiological uridine concentrations, we explored combining GSK983 with pyrimidine salvage inhibitors. We synthesized and evaluated analogs of cyclopentenyl uracil (CPU), an inhibitor of uridine salvage. We found that CPU was converted into its triphosphate in cells. When combined with GSK983, CPU resulted in large drops in cellular UTP and CTP pools. Consequently, CPU-GSK983 suppressed dengue virus replication in the presence of physiological concentrations of uridine. In addition, the CPU-GSK983 combination markedly enhanced the effect of RNA-dependent RNA polymerase (RdRp) inhibition on viral infection. Our findings highlight a new host-targeting strategy for potentiating the antiviral activity of RdRp inhibitors.
has issue date	2020-05-21(xsd:dateTime)
bibo:doi	10.1016/j.chembiol.2020.05.002
bibo:pmid	32442424
has license	no-cc
sha1sum (hex)	2ce9e1465b4ea47a3e1145b7ecd902f889132e64
schema:url	https://doi.org/10.1016/j.chembiol.2020.05.002
resource representing a document's title	Enhancing the Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with Modulators of Pyrimidine Metabolism
has PubMed Central identifier	PMC7241336
has PubMed identifier	32442424
schema:publication	Cell Chem Biol
resource representing a document's body	covid:2ce9e1465b4ea47a3e1145b7ecd902f889132e64#body_text
is schema:about of	named entity 'URACIL' named entity 'IN VITRO' named entity 'URIDINE' named entity 'uracil' named entity 'DHODH' named entity 'antiviral activity' named entity 'pyrimidine metabolism' named entity 'antiviral' named entity 'uridine' named entity 'RNA' named entity 'RNA' named entity 'Antiviral' named entity 'RNA Polymerase' named entity 'NH 3' named entity 'biological assays' named entity '3aS' named entity 'antiviral' named entity 'CPU' named entity 'potency' named entity 'NMR spectra' named entity 'UMP' named entity 'enzyme' named entity 'methylated' named entity 'uracil' named entity 'pyrimidine metabolism' named entity 'serotype' named entity 'hexanes' named entity 'RNA translation' named entity 'uridine' named entity 'D-ribose' named entity 'magnetic resonance' named entity 'antiviral activity' named entity 'virus' named entity 'NaN' named entity 'cytotoxicity' named entity '250 mM' named entity 'mmol' named entity 'viral genome replication' named entity 'phosphorylated' named entity 'CPU' named entity 'metabolism' named entity 'CPU' named entity 'physiological' named entity 'CPU' named entity 'm/z' named entity 'Chemistry' named entity 'competitive inhibitors' named entity 'replicon' named entity 'pyrimidine' named entity 'LC-MS/MS' named entity 'nucleoside diphosphate kinase' named entity 'reaction mixture' named entity '0.01' named entity 'DHODH' named entity 'treatment options' named entity 'mmol' named entity '1.2' named entity 'EtOAc' named entity 'TBAF' named entity 'intracellular' named entity 'structural genes' named entity 'TBAF' named entity 'CPU' named entity 'CPU' named entity 'mmol' named entity 'CTP synthetase' named entity 'analog' named entity 'CAD' named entity 'CPU' named entity 'm7G' named entity 'CPU' named entity 'methanol'

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