Linked Life Data

11369889

Source:http://linkedlifedata.com/resource/pubmed/id/11369889

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
Pt 6
pubmed:dateCreated
2001-5-22
pubmed:abstractText
The UL97-encoded protein kinase (pUL97) of human cytomegalovirus (HCMV) plays a critical role in the control of virus replication. Deletion of the UL97 gene results in a drastic reduction in the replication efficiency. Although the exact function of pUL97 remains unclear and its sensitivity to specific inhibitors is speculative, protein kinase inhibitors of the indolocarbazole class are effective inhibitors of cytomegalovirus. Based on the phosphorylation of ganciclovir (GCV), a novel quantification system for pUL97 kinase activity was established: the phosphorylated form of GCV exerts an easily quantifiable cytotoxic effect in transfected cells. Importantly, the addition of indolocarbazole compounds, Gö6976 and NGIC-I, which were highly effective at nanomolar concentrations while other protein kinase inhibitors were not, led to a significant reduction of pUL97 kinase activity. It was also demonstrated that a catalytically inactive mutant of pUL97, K355M, and a GCV-resistant mutant, M460I, were both negative for GCV phosphorylation, although protein phosphorylation remained detectable for the latter mutant. In vitro kinase assays were used to confirm the levels of pUL97-mediated phosphorylation recorded. To generate a tool for screening large numbers of putative inhibitors that preferentially interfere with GCV as well as protein phosphorylation, pUL97-expressing cell clones with stable pUL97 kinase activity were selected. This study demonstrates that certain indolocarbazole compounds are potent pUL97 inhibitors and, therefore, represent novel candidates for antiviral drugs that target viral protein kinase functions.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0022-1317
pubmed:author
pubmed:issnType
Print
pubmed:volume
82
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1439-50
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:11369889-Antiviral Agents, pubmed-meshheading:11369889-Carbazoles, pubmed-meshheading:11369889-Cell Line, pubmed-meshheading:11369889-Clone Cells, pubmed-meshheading:11369889-Cytomegalovirus, pubmed-meshheading:11369889-Drug Evaluation, Preclinical, pubmed-meshheading:11369889-Drug Resistance, Microbial, pubmed-meshheading:11369889-Enzyme Inhibitors, pubmed-meshheading:11369889-Ganciclovir, pubmed-meshheading:11369889-Humans, pubmed-meshheading:11369889-Indoles, pubmed-meshheading:11369889-Mutation, pubmed-meshheading:11369889-Mutation, Missense, pubmed-meshheading:11369889-Phosphorylation, pubmed-meshheading:11369889-Phosphotransferases (Alcohol Group Acceptor), pubmed-meshheading:11369889-Protein Kinase Inhibitors, pubmed-meshheading:11369889-Protein Kinases, pubmed-meshheading:11369889-Virus Replication
pubmed:year
2001
pubmed:articleTitle
Inhibitors of human cytomegalovirus replication drastically reduce the activity of the viral protein kinase pUL97.
pubmed:affiliation
Institut für Klinische und Molekulare Virologie, Universität Erlangen-Nürnberg, Schlossgarten 4, 91054 Erlangen, Germany. mdmarsch@viro.med.uni-erlangen.de
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't