Source:http://linkedlifedata.com/resource/pubmed/id/11040039
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
5
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| pubmed:dateCreated |
2000-10-30
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| pubmed:abstractText |
Cyclosaligenyl-2',3'-didehydro-2', 3'-dideoxythymidine-5'-monophosphate (cycloSal-d4TMP) is a potent and selective inhibitor of human immunodeficiency virus replication in cell culture and differs from other nucleotide prodrug approaches in that it is designed to selectively deliver the nucleotide 5'-monophosphate by a controlled, chemically induced hydrolysis. Its antiviral efficacy in cell culture is at least as good as, if not superior to, that of d4T. CycloSal-d4TMP was found to lead to the efficient intracellular release of d4TMP in a variety of cell lines, including both wild-type CEM and thymidine kinase-deficient CEM/TK(-) cells. Under similar experimental conditions, exposure of CEM/TK(-) cells to d4T failed to result in significant d4TTP levels. The intracellular conversion of cycloSal-d4TMP proved to be both time and dose dependent. The half-life of d4TTP generated intracellularly from d4T- or cycloSal-d4TMP-treated CEM cells was approximately 3.5 h, and the intracellular ratios of d4TTP/d4TMP in cells exposed to cycloSal-d4TMP gradually increased from 1 to 3.4 upon prolonged incubation. Radiolabeled cycloSal-d4TMP could be separated as its two R(p) and S(p) diastereomers on high-performance liquid chromatography. The R(p) diastereomer of cycloSal-d4TMP was 3- to 7-fold more efficient in releasing d4TMP and generating d4TTP than the S(p) cycloSal-d4TMP diastereomer. This correlated well with the 5-fold more pronounced antiviral activity of the R(p) diastereomer versus the S(p) diastereomer. d4TMP is a poor substrate for the cytosolic 5'(3')-deoxyribonucleotidase (V(max)/K(m) for d4TMP: 0.08 of V(max)/K(m) for dTMP) and is only slowly hydrolyzed to d4T. This contributes to the efficient conversion of the prodrug of d4TTP.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/2',3'-dideoxy-2',3'-didehydrothymidi...,
http://linkedlifedata.com/resource/pubmed/chemical/3'-azido-3'-deoxythymidine...,
http://linkedlifedata.com/resource/pubmed/chemical/5'(3')-nucleotidase,
http://linkedlifedata.com/resource/pubmed/chemical/5'-Nucleotidase,
http://linkedlifedata.com/resource/pubmed/chemical/Anti-HIV Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Culture Media,
http://linkedlifedata.com/resource/pubmed/chemical/Dideoxynucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/Stavudine,
http://linkedlifedata.com/resource/pubmed/chemical/Thymidine,
http://linkedlifedata.com/resource/pubmed/chemical/Thymidine Kinase,
http://linkedlifedata.com/resource/pubmed/chemical/Thymidine Monophosphate,
http://linkedlifedata.com/resource/pubmed/chemical/Thymine Nucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/Tritium,
http://linkedlifedata.com/resource/pubmed/chemical/Zidovudine
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| pubmed:status |
MEDLINE
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| pubmed:month |
Nov
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| pubmed:issn |
0026-895X
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:volume |
58
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
928-35
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| pubmed:dateRevised |
2007-11-15
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| pubmed:meshHeading |
pubmed-meshheading:11040039-5'-Nucleotidase,
pubmed-meshheading:11040039-Anti-HIV Agents,
pubmed-meshheading:11040039-Culture Media,
pubmed-meshheading:11040039-Dideoxynucleotides,
pubmed-meshheading:11040039-Half-Life,
pubmed-meshheading:11040039-Humans,
pubmed-meshheading:11040039-Hydrogen-Ion Concentration,
pubmed-meshheading:11040039-Leukocytes, Mononuclear,
pubmed-meshheading:11040039-Macrophages,
pubmed-meshheading:11040039-Monocytes,
pubmed-meshheading:11040039-Stavudine,
pubmed-meshheading:11040039-Thymidine,
pubmed-meshheading:11040039-Thymidine Kinase,
pubmed-meshheading:11040039-Thymidine Monophosphate,
pubmed-meshheading:11040039-Thymine Nucleotides,
pubmed-meshheading:11040039-Time Factors,
pubmed-meshheading:11040039-Tritium,
pubmed-meshheading:11040039-Tumor Cells, Cultured,
pubmed-meshheading:11040039-Zidovudine
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| pubmed:year |
2000
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| pubmed:articleTitle |
Cyclosaligenyl-2',3'-didehydro-2',3'-dideoxythymidine monophosphate: efficient intracellular delivery of d4TMP.
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| pubmed:affiliation |
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium. jan.balzarini@rega.kuleuven.ac.be
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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