| pubmed-article:18056278 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:18056278 | lifeskim:mentions | umls-concept:C0001407 | lld:lifeskim |
| pubmed-article:18056278 | lifeskim:mentions | umls-concept:C0286079 | lld:lifeskim |
| pubmed-article:18056278 | lifeskim:mentions | umls-concept:C1704973 | lld:lifeskim |
| pubmed-article:18056278 | lifeskim:mentions | umls-concept:C0243077 | lld:lifeskim |
| pubmed-article:18056278 | lifeskim:mentions | umls-concept:C1705542 | lld:lifeskim |
| pubmed-article:18056278 | lifeskim:mentions | umls-concept:C0205250 | lld:lifeskim |
| pubmed-article:18056278 | lifeskim:mentions | umls-concept:C1704419 | lld:lifeskim |
| pubmed-article:18056278 | lifeskim:mentions | umls-concept:C0291196 | lld:lifeskim |
| pubmed-article:18056278 | pubmed:issue | 2 | lld:pubmed |
| pubmed-article:18056278 | pubmed:dateCreated | 2008-1-24 | lld:pubmed |
| pubmed-article:18056278 | pubmed:abstractText | The acyclic nucleoside phosphonate drug (S)-9-[3-hydroxy-(2-phosphonomethoxy)propyl]adenine [(S)-HPMPA], is a broad-spectrum antiviral and antiparasitic agent. Previous work has shown that the active intracellular metabolite of this compound, (S)-HPMPA diphosphate [(S)-HPMPApp], is an analog of dATP and targets DNA polymerases. However, the mechanism by which (S)-HPMPA inhibits DNA polymerases remains elusive. Using vaccinia virus as a model system, we have previously shown that cidofovir diphosphate (CDVpp), an analog of dCTP and a related antiviral agent, is a poor substrate for the vaccinia virus DNA polymerase and acts to inhibit primer extension and block 3'-to-5' proofreading exonuclease activity. Based on structural similarities and the greater antiviral efficacy of (S)-HPMPA, we predicted that (S)-HPMPApp would have a similar, but more pronounced effect on vaccinia polymerase than CDVpp. Interestingly, we found that (S)-HPMPApp is a good substrate for the viral enzyme, exhibiting K(m) and V(max) parameters comparable to those of dATP, and certainly not behaving like CDVpp as a functional chain terminator. Metabolic experiments indicated that (S)-HPMPA is converted to (S)-HPMPApp to a much greater extent than CDV is converted to CDVpp, although both drugs cause identical effects on virus DNA replication at their 50% effective concentration. Subsequent studies showed that both compounds can be faithfully incorporated into DNA, but when CDV and (S)-HPMPA are incorporated into the template strand, both strongly inhibit trans-lesion DNA synthesis. It thus appears that nucleoside phosphonate drugs exhibit at least two different effects on DNA polymerases depending upon in what form the enzyme encounters the drug. | lld:pubmed |
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| pubmed-article:18056278 | pubmed:language | eng | lld:pubmed |
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| pubmed-article:18056278 | pubmed:citationSubset | IM | lld:pubmed |
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| pubmed-article:18056278 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:18056278 | pubmed:month | Feb | lld:pubmed |
| pubmed-article:18056278 | pubmed:issn | 0066-4804 | lld:pubmed |
| pubmed-article:18056278 | pubmed:author | pubmed-author:HostetlerKarl... | lld:pubmed |
| pubmed-article:18056278 | pubmed:author | pubmed-author:EvansDavid... | lld:pubmed |
| pubmed-article:18056278 | pubmed:author | pubmed-author:AldernKathy... | lld:pubmed |
| pubmed-article:18056278 | pubmed:author | pubmed-author:MageeWendy... | lld:pubmed |
| pubmed-article:18056278 | pubmed:issnType | Print | lld:pubmed |
| pubmed-article:18056278 | pubmed:volume | 52 | lld:pubmed |
| pubmed-article:18056278 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:18056278 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:18056278 | pubmed:pagination | 586-97 | lld:pubmed |
| pubmed-article:18056278 | pubmed:dateRevised | 2011-2-16 | lld:pubmed |
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| pubmed-article:18056278 | pubmed:meshHeading | pubmed-meshheading:18056278... | lld:pubmed |
| pubmed-article:18056278 | pubmed:year | 2008 | lld:pubmed |
| pubmed-article:18056278 | pubmed:articleTitle | Cidofovir and (S)-9-[3-hydroxy-(2-phosphonomethoxy)propyl]adenine are highly effective inhibitors of vaccinia virus DNA polymerase when incorporated into the template strand. | lld:pubmed |
| pubmed-article:18056278 | pubmed:affiliation | Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, 141 Medical Sciences Bldg., Edmonton, Alberta T6G 2H7, Canada. | lld:pubmed |
| pubmed-article:18056278 | pubmed:publicationType | Journal Article | lld:pubmed |
| pubmed-article:18056278 | pubmed:publicationType | Research Support, Non-U.S. Gov't | lld:pubmed |
| pubmed-article:18056278 | pubmed:publicationType | Research Support, N.I.H., Extramural | lld:pubmed |
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