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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
16
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pubmed:dateCreated |
2009-11-2
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pubmed:abstractText |
The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for inhibition. Herein, we present 1H-benzo[de]isoquinoline-1,3(2H)-diones as a new series of selective inhibitors of HCV NS5B polymerase. The HTS hit 1 shows submicromolar potency in two different HCV replicons (1b and 2b) and displays no activity on other polymerases (HIV-RT, Polio-pol, GBV-b-pol). These inhibitors act during the pre-elongation phase by binding to NS5B non-nucleoside binding site Thumb Site II as demonstrated by crystal structure of compound 1 with the DeltaC55-1b and DeltaC21-2b enzymes and by mutagenesis studies. SAR in this new series reveals inhibitors, such as 20, with low micromolar activity in the HCV replicon and with good activity/toxicity window in cells.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:AltamuraSergioS,
pubmed-author:AttenniBarbaraB,
pubmed-author:CarfìAndreaA,
pubmed-author:CarrollSteve SSS,
pubmed-author:De FrancescoRaffaeleR,
pubmed-author:Di MarcoStefaniaS,
pubmed-author:GennariNadiaN,
pubmed-author:LORDR MRM,
pubmed-author:MalanconaSavinaS,
pubmed-author:Martin HernandoJosé IJI,
pubmed-author:MigliaccioGiovanniG,
pubmed-author:NarjesFrankF,
pubmed-author:OlsenDavid BDB,
pubmed-author:OntoriaJesus MJM,
pubmed-author:RowleyMichaelM,
pubmed-author:RydbergEdwin HEH,
pubmed-author:SummaVincenzoV,
pubmed-author:TomeiLiciaL
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pubmed:issnType |
Electronic
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pubmed:day |
27
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pubmed:volume |
52
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
5217-27
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:19877603-Administration, Oral,
pubmed-meshheading:19877603-Animals,
pubmed-meshheading:19877603-Antiviral Agents,
pubmed-meshheading:19877603-Binding Sites,
pubmed-meshheading:19877603-Biological Availability,
pubmed-meshheading:19877603-Cell Line, Tumor,
pubmed-meshheading:19877603-Crystallography, X-Ray,
pubmed-meshheading:19877603-Drug Resistance, Viral,
pubmed-meshheading:19877603-Genotype,
pubmed-meshheading:19877603-Hepacivirus,
pubmed-meshheading:19877603-Humans,
pubmed-meshheading:19877603-Hydrogen Bonding,
pubmed-meshheading:19877603-Hydrophobic and Hydrophilic Interactions,
pubmed-meshheading:19877603-Isoquinolines,
pubmed-meshheading:19877603-Models, Molecular,
pubmed-meshheading:19877603-Molecular Structure,
pubmed-meshheading:19877603-Mutation,
pubmed-meshheading:19877603-Rats,
pubmed-meshheading:19877603-Replicon,
pubmed-meshheading:19877603-Structure-Activity Relationship,
pubmed-meshheading:19877603-Viral Nonstructural Proteins,
pubmed-meshheading:19877603-Virus Replication
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pubmed:year |
2009
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pubmed:articleTitle |
Identification and biological evaluation of a series of 1H-benzo[de]isoquinoline-1,3(2H)-diones as hepatitis C virus NS5B polymerase inhibitors.
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pubmed:affiliation |
Istituto Di Ricerche Di Biologia Molecolare, P. Angeletti, S.p.A. (IRBM-MRL Rome), Via Pontina Km 30,600, I-00040 Pomezia, Italy. jesus_ontoria@merck.com
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pubmed:publicationType |
Journal Article
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