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rdf:type |
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lifeskim:mentions |
umls-concept:C0007600,
umls-concept:C0017279,
umls-concept:C0019704,
umls-concept:C0033268,
umls-concept:C0086418,
umls-concept:C0086574,
umls-concept:C0090240,
umls-concept:C0243126,
umls-concept:C0887913,
umls-concept:C1514570,
umls-concept:C1709634
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pubmed:issue |
6
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pubmed:dateCreated |
1991-4-25
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pubmed:abstractText |
Covalent linkage of myristate (tetradecanoate; 14:0) to the NH2-terminal glycine residue of the human immunodeficiency virus 1 (HIV-1) 55-kDa gag polyprotein precursor (Pr55gag) is necessary for its proteolytic processing and viral assembly. We have shown recently that several analogs of myristate in which a methylene group is replaced by a single oxygen or sulfur atom are substrates for Saccharomyces cerevisiae and mammalian myristoyl-CoA:protein N-myristoyltransferase (EC 2.3.1.97; NMT) despite their reduced hydrophobicity. Some inhibit HIV-1 replication in acutely infected CD4+H9 cells without accompanying cellular toxicity. To examine the mechanism of their antiviral effects, we performed labeling studies with two analogs, 12-methoxydodecanoate (13-oxamyristate; 13-OxaMyr) and 5-octyloxypentanoate (6-oxamyristate; 6-OxaMyr), the former being much more effective than the latter in blocking virus production. [3H]Myristate and [3H]13-OxaMyr were incorporated into Pr55gag with comparable efficiency when it was coexpressed with S. cerevisiae NMT in Escherichia coli. [3H]6-OxaMyr was not incorporated, even though its substrate properties in vitro were similar to those of 13-OxaMyr and myristate. [3H]13-OxaMyr, but not [3H]6-OxaMyr, was also efficiently incorporated into HIV-1 Pr55gag and nef (negative factor) in chronically infected H9 cells. Analog incorporation produced a redistribution of Pr55gag from membrane to cytosolic fractions and markedly decreased its proteolytic processing by viral protease. 13-OxaMyr and 3'-azido-3'-deoxythymidine (AZT) act synergistically to reduce virus production in acutely infected H9 cells. Unlike AZT, the analog is able to inhibit virus production (up to 70%) in chronically infected H9 cells. Moreover, the inhibitory effect lasts 6-8 days. These results suggest that (i) its mechanism of action is distinct from that of AZT and involves a late step in virus assembly; (ii) the analog may allow reduction in the dose of AZT required to affect viral replication; and (iii) combinations of analog and HIV-1 protease inhibitors may have synergistic effects on the processing of Pr55gag.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/2006142-2107025,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2006142-2198291,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2006142-2236060,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2006142-2405382,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2006142-2406721,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2006142-2447506,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2006142-2645523,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2006142-2657103,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2006142-2669897,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2006142-2784195,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2006142-2788277,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2006142-2813417,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2006142-3001045,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2006142-3014663,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2006142-3040055,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2006142-3118220,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2006142-3123712,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2006142-3143109,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2006142-3321060,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2006142-5432063,
http://linkedlifedata.com/resource/pubmed/commentcorrection/2006142-6261256
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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 |
Mar
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pubmed:issn |
0027-8424
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
88
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
2055-9
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
pubmed-meshheading:2006142-Antiviral Agents,
pubmed-meshheading:2006142-Cell Line,
pubmed-meshheading:2006142-Cell Survival,
pubmed-meshheading:2006142-Cell Transformation, Viral,
pubmed-meshheading:2006142-Escherichia coli,
pubmed-meshheading:2006142-Gene Products, gag,
pubmed-meshheading:2006142-Genetic Vectors,
pubmed-meshheading:2006142-HIV-1,
pubmed-meshheading:2006142-Humans,
pubmed-meshheading:2006142-Kinetics,
pubmed-meshheading:2006142-Laurates,
pubmed-meshheading:2006142-Plasmids,
pubmed-meshheading:2006142-Protein Precursors,
pubmed-meshheading:2006142-Protein Processing, Post-Translational,
pubmed-meshheading:2006142-Saccharomyces cerevisiae,
pubmed-meshheading:2006142-Virus Replication,
pubmed-meshheading:2006142-Zidovudine
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pubmed:year |
1991
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pubmed:articleTitle |
Incorporation of 12-methoxydodecanoate into the human immunodeficiency virus 1 gag polyprotein precursor inhibits its proteolytic processing and virus production in a chronically infected human lymphoid cell line.
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pubmed:affiliation |
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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