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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
11
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pubmed:dateCreated |
1992-7-8
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pubmed:abstractText |
Several novel imidotriphosphate analogues of thymidine have been synthesized and have been shown to be effective inhibitors of human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT). When the alpha,beta-bridging oxygens of thymidine triphosphate (TTP) and 3'-azido-3'-deoxythymidine 5'-triphosphate (AZTTP) were replaced by a nitrogen, the resulting analogues were no longer substrates but instead became competitive inhibitors of HIV-1 RT. The most potent of the alpha,beta-imidotriphosphate derivatives tested was thymidine 5'-[alpha,beta-imido]triphosphate (TMPNPP, 1a). This analogue has a Ki value of 2.4 microM, inhibiting HIV-1 RT 400-fold more potently than it inhibits DNA polymerase I large fragment (Klenow). 3'-Azido-3'-deoxythymidine 5'-[alpha,beta-imido]triphosphate (AZTMPNPP, 1b) gave a Ki value about 10-fold greater than that for TMPNPP, indicating that a 3'-azido substituent decreases the affinity of AZTTP to HIV-1 RT relative to the normal 3'-OH substituent. Dideoxythymidine 5'-[alpha,beta-imido]triphosphate (ddTMPNPP, 1c) was intermediate in potency, giving a Ki value of 15 microM. In contrast, substitution at the beta,gamma-bridging oxygen by nitrogen did not block the enzymatic cleavage of the adjacent alpha,beta-phosphate linkage, and 3'-azidothymidine 5'-[beta,gamma-imido]triphosphate (AZTMPPNP, 1e), the 5'-[beta,gamma-imido]triphosphate analogue of AZTTP, is therefore both a substrate for and a potent inhibitor of HIV-1 RT with an observed Ki value of 87 nM. Further nitrogen substitution of the bridging oxygens in the phosphate chain decreases the inhibitory potency by approximately 10-fold, as in the case of thymidine 5'-[alpha,beta:beta,gamma-diimido]triphosphate (TMPNPNP, 1d).
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Dideoxynucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/RNA-Directed DNA Polymerase,
http://linkedlifedata.com/resource/pubmed/chemical/Reverse Transcriptase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Thymine Nucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/Zidovudine,
http://linkedlifedata.com/resource/pubmed/chemical/thymidine 5'-triphosphate
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
0022-2623
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
29
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pubmed:volume |
35
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1938-41
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pubmed:dateRevised |
2007-11-15
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pubmed:meshHeading |
pubmed-meshheading:1375962-Binding, Competitive,
pubmed-meshheading:1375962-Dideoxynucleotides,
pubmed-meshheading:1375962-HIV-1,
pubmed-meshheading:1375962-Molecular Structure,
pubmed-meshheading:1375962-RNA-Directed DNA Polymerase,
pubmed-meshheading:1375962-Reverse Transcriptase Inhibitors,
pubmed-meshheading:1375962-Structure-Activity Relationship,
pubmed-meshheading:1375962-Thymine Nucleotides,
pubmed-meshheading:1375962-Zidovudine
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pubmed:year |
1992
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pubmed:articleTitle |
New thymidine triphosphate analogue inhibitors of human immunodeficiency virus-1 reverse transcriptase.
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pubmed:affiliation |
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143.
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pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, U.S. Gov't, P.H.S.
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