Source:http://linkedlifedata.com/resource/pubmed/id/20470829
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
2
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pubmed:dateCreated |
2010-7-20
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pubmed:abstractText |
Dengue virus (DENV), an emerging pathogen from the Flaviviridae family with neither vaccine nor antiviral treatment available, causes a serious worldwide public health threat. In theory, there are several ways by which small molecules could inhibit the replication cycle of DENV. Here, we show that the nucleoside analogue beta-d-2'-ethynyl-7-deaza-adenosine inhibits representative strains of all four serotypes of DENV with an EC(50) around or below 1microM. Using membrane-associated native replicase complex as well as recombinant RNA polymerase from each DENV serotype in enzymatic assays, we provide evidence that beta-d-2'-ethynyl-7-deaza-adenosine triphosphate (2'E-7D-ATP) targets viral replication at the polymerase active site by competing with the natural nucleotide substrate with an apparent K(i) of 0.060+/-0.016microM. In single-nucleotide incorporation experiments, the catalytic efficiency of 2'E-7D-ATP is 10-fold lower than for natural ATP, and the incorporated nucleotide analogue causes immediate chain termination. A combination of bioinformatics and site-directed mutagenesis demonstrates that 2'E-7D-ATP is equipotent across all serotypes because the nucleotide binding site residues are conserved in dengue virus. Overall, beta-d-2'-ethynyl-7-deaza-adenosine provides a promising scaffold for the development of inhibitors of dengue virus polymerase.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical | |
pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
1872-9096
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pubmed:author |
pubmed-author:DevalJeromeJ,
pubmed-author:GeePeterP,
pubmed-author:HarrisSeth FSF,
pubmed-author:HeilekGabrielleG,
pubmed-author:HenningsenRobertR,
pubmed-author:JavanbakhtHassanH,
pubmed-author:JekleAndreasA,
pubmed-author:KlumppKlausK,
pubmed-author:KutachAlan KAK,
pubmed-author:LatourDerek RDR,
pubmed-author:LokStephen JSJ,
pubmed-author:LoyEE,
pubmed-author:PenG BGB,
pubmed-author:RenSupingS,
pubmed-author:ShawDavidD,
pubmed-author:SwinneyDavid CDC,
pubmed-author:TranPatriciaP,
pubmed-author:WangSandra MSM
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pubmed:copyrightInfo |
Copyright 2010 Elsevier B.V. All rights reserved.
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pubmed:issnType |
Electronic
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pubmed:volume |
87
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
213-22
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pubmed:meshHeading |
pubmed-meshheading:20470829-Adenosine Triphosphate,
pubmed-meshheading:20470829-Animals,
pubmed-meshheading:20470829-Antiviral Agents,
pubmed-meshheading:20470829-Binding Sites,
pubmed-meshheading:20470829-Cell Line,
pubmed-meshheading:20470829-Computational Biology,
pubmed-meshheading:20470829-Conserved Sequence,
pubmed-meshheading:20470829-Cricetinae,
pubmed-meshheading:20470829-DNA-Directed RNA Polymerases,
pubmed-meshheading:20470829-Dengue Virus,
pubmed-meshheading:20470829-Enzyme Inhibitors,
pubmed-meshheading:20470829-Microbial Sensitivity Tests,
pubmed-meshheading:20470829-Molecular Structure,
pubmed-meshheading:20470829-Mutagenesis, Site-Directed
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pubmed:year |
2010
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pubmed:articleTitle |
Biochemical characterization of the inhibition of the dengue virus RNA polymerase by beta-d-2'-ethynyl-7-deaza-adenosine triphosphate.
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pubmed:affiliation |
Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA, United States.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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