Incorporation of the carbocyclic analog of 2'-deoxyguanosine into the DNA of herpes simplex virus and of HEp-2 cells infected with herpes simplex virus
The carbocyclic analog of 2'-deoxyguanosine (CdG) is active against herpes simplex virus (HSV), human cytomegalovirus, and human hepatitis-B virus. In order to understand the mechanism of action of this compound against HSV, we have evaluated (a) the incorporation of [3H]CdG into viral and host...
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| Veröffentlicht in: | Molecular pharmacology 1992-02, Vol.41 (2), p.245-251 |
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| creator | W B Parker S C Shaddix P W Allan G Arnett L M Rose W M Shannon Y F Shealy J A Montgomery J A Secrist, 3rd L L Bennett, Jr |
| description | The carbocyclic analog of 2'-deoxyguanosine (CdG) is active against herpes simplex virus (HSV), human cytomegalovirus, and
human hepatitis-B virus. In order to understand the mechanism of action of this compound against HSV, we have evaluated (a)
the incorporation of [3H]CdG into viral and host DNA in HEp-2 cells infected with HSV and (b) the interaction of the 5'-triphosphate
of CdG (CdG-TP) with the HSV DNA polymerase and human DNA polymerases alpha, beta, and gamma (EC 2.7.7.7). Incubation of HSV-1-infected
HEp-2 cells with [3H]CdG resulted in the incorporation of CdG into both the HSV and the host cell DNA. These results indicated
that CdG-TP was used as a substrate for HSV DNA polymerase and for at least one of the cellular DNA polymerases. Degradation
of both viral and host DNA with micrococcal nuclease and spleen phosphodiesterase indicated that CdG was incorporated primarily
into internal positions in both DNAs. The viral DNA containing CdG sedimented in neutral and alkaline sucrose gradients in
the same way as did viral DNA labeled with [3H]thymidine, indicating that the HSV DNA containing CdG was similar in size to
untreated HSV DNA. CdG-TP was a competitive inhibitor of the incorporation of dGTP into DNA by the HSV DNA polymerase (Ki
of 0.35 microM) and the human DNA polymerase alpha (Ki of 1 microM). CdG-TP was not a potent inhibitor of either DNA polymerase
beta or gamma. Using DNA-sequencing technology, CdG-TP was found to be an efficient substrate for HSV DNA polymerase. Incorporation
of CdG monophosphate (CdG-MP) into the DNA by HSV DNA polymerase did not interfere with subsequent chain extension. These
results suggested that the antiviral activity of CdG was due to its incorporation into the DNA and subsequent disruption of
viral functions. In contrast, CdG-TP was not as good as dGTP as a substrate for DNA synthesis by DNA polymerase alpha, and
incorporation of CdG-MP by DNA polymerase alpha inhibited further DNA chain elongation. |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_highw</sourceid><recordid>TN_cdi_highwire_pharmacology_41_2_245</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>72826263</sourcerecordid><originalsourceid>FETCH-LOGICAL-h267t-6c5d1e51a73327e7f5df1ef4424959ed27367aa53876cd89d3367008ba294b923</originalsourceid><addsrcrecordid>eNqNkc-O0zAQhyMEWsrCIyD5AhxQJP-Nk2NVlu1KFVxA4hY59qQxSuxgO9vtk-zr4m4rTkgwF2v0-77RyPOsWBFBSYkJIc-LFca0KutG_HhZvIrxJ8aEixpfFVeEEcKxXBWPd077MPugkvUO-R6lAZBWofP6qEerkXJq9PtTQj-UBvzDcb8o56N1gKxL_kn49GV9IgYIM0QU7TSP8IDubVhiHmBO2fZmLinSMI4xez3oBAYdbBr-ar0uXvRqjPDm8l4X3z_ffNtsy93X27vNelcOtJKprLQwBARRkjEqQfbC9AR6zilvRAOGSlZJpQSrZaVN3RiWe4zrTtGGdw1l18X789w5-F8LxNRONp6WVA78EltJa1rRiv0TJFUtJJMkg28v4NJNYNo52EmFY3v58pzX5_wAne-jtuA0_KHWpGnodsclxbnExqanw2z84lJWP_6_mul3Z3qw--FgQyYHFSalfb7nseWkpS3lgv0GaiCtJw</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>16857371</pqid></control><display><type>article</type><title>Incorporation of the carbocyclic analog of 2'-deoxyguanosine into the DNA of herpes simplex virus and of HEp-2 cells infected with herpes simplex virus</title><source>Web of Science - Science Citation Index Expanded - 1992<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /></source><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><creator>W B Parker ; S C Shaddix ; P W Allan ; G Arnett ; L M Rose ; W M Shannon ; Y F Shealy ; J A Montgomery ; J A Secrist, 3rd ; L L Bennett, Jr</creator><creatorcontrib>W B Parker ; S C Shaddix ; P W Allan ; G Arnett ; L M Rose ; W M Shannon ; Y F Shealy ; J A Montgomery ; J A Secrist, 3rd ; L L Bennett, Jr</creatorcontrib><description>The carbocyclic analog of 2'-deoxyguanosine (CdG) is active against herpes simplex virus (HSV), human cytomegalovirus, and
human hepatitis-B virus. In order to understand the mechanism of action of this compound against HSV, we have evaluated (a)
the incorporation of [3H]CdG into viral and host DNA in HEp-2 cells infected with HSV and (b) the interaction of the 5'-triphosphate
of CdG (CdG-TP) with the HSV DNA polymerase and human DNA polymerases alpha, beta, and gamma (EC 2.7.7.7). Incubation of HSV-1-infected
HEp-2 cells with [3H]CdG resulted in the incorporation of CdG into both the HSV and the host cell DNA. These results indicated
that CdG-TP was used as a substrate for HSV DNA polymerase and for at least one of the cellular DNA polymerases. Degradation
of both viral and host DNA with micrococcal nuclease and spleen phosphodiesterase indicated that CdG was incorporated primarily
into internal positions in both DNAs. The viral DNA containing CdG sedimented in neutral and alkaline sucrose gradients in
the same way as did viral DNA labeled with [3H]thymidine, indicating that the HSV DNA containing CdG was similar in size to
untreated HSV DNA. CdG-TP was a competitive inhibitor of the incorporation of dGTP into DNA by the HSV DNA polymerase (Ki
of 0.35 microM) and the human DNA polymerase alpha (Ki of 1 microM). CdG-TP was not a potent inhibitor of either DNA polymerase
beta or gamma. Using DNA-sequencing technology, CdG-TP was found to be an efficient substrate for HSV DNA polymerase. Incorporation
of CdG monophosphate (CdG-MP) into the DNA by HSV DNA polymerase did not interfere with subsequent chain extension. These
results suggested that the antiviral activity of CdG was due to its incorporation into the DNA and subsequent disruption of
viral functions. In contrast, CdG-TP was not as good as dGTP as a substrate for DNA synthesis by DNA polymerase alpha, and
incorporation of CdG-MP by DNA polymerase alpha inhibited further DNA chain elongation.</description><identifier>ISSN: 0026-895X</identifier><identifier>EISSN: 1521-0111</identifier><identifier>PMID: 1311407</identifier><language>eng</language><publisher>BALTIMORE: American Society for Pharmacology and Experimental Therapeutics</publisher><subject>Base Sequence ; Deoxyguanine Nucleotides - metabolism ; Deoxyguanosine - analogs & derivatives ; Deoxyguanosine - metabolism ; DNA, Viral - drug effects ; DNA, Viral - metabolism ; Herpes Simplex - metabolism ; herpes simplex virus 1 ; Humans ; Life Sciences & Biomedicine ; Molecular Sequence Data ; Nucleic Acid Synthesis Inhibitors ; Pharmacology & Pharmacy ; Science & Technology ; Simplexvirus - metabolism ; Tritium ; Viral Proteins - antagonists & inhibitors</subject><ispartof>Molecular pharmacology, 1992-02, Vol.41 (2), p.245-251</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>5</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wosA1992HL47200005</woscitedreferencesoriginalsourcerecordid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786,27199</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1311407$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>W B Parker</creatorcontrib><creatorcontrib>S C Shaddix</creatorcontrib><creatorcontrib>P W Allan</creatorcontrib><creatorcontrib>G Arnett</creatorcontrib><creatorcontrib>L M Rose</creatorcontrib><creatorcontrib>W M Shannon</creatorcontrib><creatorcontrib>Y F Shealy</creatorcontrib><creatorcontrib>J A Montgomery</creatorcontrib><creatorcontrib>J A Secrist, 3rd</creatorcontrib><creatorcontrib>L L Bennett, Jr</creatorcontrib><title>Incorporation of the carbocyclic analog of 2'-deoxyguanosine into the DNA of herpes simplex virus and of HEp-2 cells infected with herpes simplex virus</title><title>Molecular pharmacology</title><addtitle>MOL PHARMACOL</addtitle><addtitle>Mol Pharmacol</addtitle><description>The carbocyclic analog of 2'-deoxyguanosine (CdG) is active against herpes simplex virus (HSV), human cytomegalovirus, and
human hepatitis-B virus. In order to understand the mechanism of action of this compound against HSV, we have evaluated (a)
the incorporation of [3H]CdG into viral and host DNA in HEp-2 cells infected with HSV and (b) the interaction of the 5'-triphosphate
of CdG (CdG-TP) with the HSV DNA polymerase and human DNA polymerases alpha, beta, and gamma (EC 2.7.7.7). Incubation of HSV-1-infected
HEp-2 cells with [3H]CdG resulted in the incorporation of CdG into both the HSV and the host cell DNA. These results indicated
that CdG-TP was used as a substrate for HSV DNA polymerase and for at least one of the cellular DNA polymerases. Degradation
of both viral and host DNA with micrococcal nuclease and spleen phosphodiesterase indicated that CdG was incorporated primarily
into internal positions in both DNAs. The viral DNA containing CdG sedimented in neutral and alkaline sucrose gradients in
the same way as did viral DNA labeled with [3H]thymidine, indicating that the HSV DNA containing CdG was similar in size to
untreated HSV DNA. CdG-TP was a competitive inhibitor of the incorporation of dGTP into DNA by the HSV DNA polymerase (Ki
of 0.35 microM) and the human DNA polymerase alpha (Ki of 1 microM). CdG-TP was not a potent inhibitor of either DNA polymerase
beta or gamma. Using DNA-sequencing technology, CdG-TP was found to be an efficient substrate for HSV DNA polymerase. Incorporation
of CdG monophosphate (CdG-MP) into the DNA by HSV DNA polymerase did not interfere with subsequent chain extension. These
results suggested that the antiviral activity of CdG was due to its incorporation into the DNA and subsequent disruption of
viral functions. In contrast, CdG-TP was not as good as dGTP as a substrate for DNA synthesis by DNA polymerase alpha, and
incorporation of CdG-MP by DNA polymerase alpha inhibited further DNA chain elongation.</description><subject>Base Sequence</subject><subject>Deoxyguanine Nucleotides - metabolism</subject><subject>Deoxyguanosine - analogs & derivatives</subject><subject>Deoxyguanosine - metabolism</subject><subject>DNA, Viral - drug effects</subject><subject>DNA, Viral - metabolism</subject><subject>Herpes Simplex - metabolism</subject><subject>herpes simplex virus 1</subject><subject>Humans</subject><subject>Life Sciences & Biomedicine</subject><subject>Molecular Sequence Data</subject><subject>Nucleic Acid Synthesis Inhibitors</subject><subject>Pharmacology & Pharmacy</subject><subject>Science & Technology</subject><subject>Simplexvirus - metabolism</subject><subject>Tritium</subject><subject>Viral Proteins - antagonists & inhibitors</subject><issn>0026-895X</issn><issn>1521-0111</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1992</creationdate><recordtype>article</recordtype><sourceid>EZCTM</sourceid><sourceid>EIF</sourceid><recordid>eNqNkc-O0zAQhyMEWsrCIyD5AhxQJP-Nk2NVlu1KFVxA4hY59qQxSuxgO9vtk-zr4m4rTkgwF2v0-77RyPOsWBFBSYkJIc-LFca0KutG_HhZvIrxJ8aEixpfFVeEEcKxXBWPd077MPugkvUO-R6lAZBWofP6qEerkXJq9PtTQj-UBvzDcb8o56N1gKxL_kn49GV9IgYIM0QU7TSP8IDubVhiHmBO2fZmLinSMI4xez3oBAYdbBr-ar0uXvRqjPDm8l4X3z_ffNtsy93X27vNelcOtJKprLQwBARRkjEqQfbC9AR6zilvRAOGSlZJpQSrZaVN3RiWe4zrTtGGdw1l18X789w5-F8LxNRONp6WVA78EltJa1rRiv0TJFUtJJMkg28v4NJNYNo52EmFY3v58pzX5_wAne-jtuA0_KHWpGnodsclxbnExqanw2z84lJWP_6_mul3Z3qw--FgQyYHFSalfb7nseWkpS3lgv0GaiCtJw</recordid><startdate>19920201</startdate><enddate>19920201</enddate><creator>W B Parker</creator><creator>S C Shaddix</creator><creator>P W Allan</creator><creator>G Arnett</creator><creator>L M Rose</creator><creator>W M Shannon</creator><creator>Y F Shealy</creator><creator>J A Montgomery</creator><creator>J A Secrist, 3rd</creator><creator>L L Bennett, Jr</creator><general>American Society for Pharmacology and Experimental Therapeutics</general><general>Lippincott Williams & Wilkins</general><scope>BLEPL</scope><scope>DTL</scope><scope>EZCTM</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7U9</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>19920201</creationdate><title>Incorporation of the carbocyclic analog of 2'-deoxyguanosine into the DNA of herpes simplex virus and of HEp-2 cells infected with herpes simplex virus</title><author>W B Parker ; S C Shaddix ; P W Allan ; G Arnett ; L M Rose ; W M Shannon ; Y F Shealy ; J A Montgomery ; J A Secrist, 3rd ; L L Bennett, Jr</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h267t-6c5d1e51a73327e7f5df1ef4424959ed27367aa53876cd89d3367008ba294b923</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1992</creationdate><topic>Base Sequence</topic><topic>Deoxyguanine Nucleotides - metabolism</topic><topic>Deoxyguanosine - analogs & derivatives</topic><topic>Deoxyguanosine - metabolism</topic><topic>DNA, Viral - drug effects</topic><topic>DNA, Viral - metabolism</topic><topic>Herpes Simplex - metabolism</topic><topic>herpes simplex virus 1</topic><topic>Humans</topic><topic>Life Sciences & Biomedicine</topic><topic>Molecular Sequence Data</topic><topic>Nucleic Acid Synthesis Inhibitors</topic><topic>Pharmacology & Pharmacy</topic><topic>Science & Technology</topic><topic>Simplexvirus - metabolism</topic><topic>Tritium</topic><topic>Viral Proteins - antagonists & inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>W B Parker</creatorcontrib><creatorcontrib>S C Shaddix</creatorcontrib><creatorcontrib>P W Allan</creatorcontrib><creatorcontrib>G Arnett</creatorcontrib><creatorcontrib>L M Rose</creatorcontrib><creatorcontrib>W M Shannon</creatorcontrib><creatorcontrib>Y F Shealy</creatorcontrib><creatorcontrib>J A Montgomery</creatorcontrib><creatorcontrib>J A Secrist, 3rd</creatorcontrib><creatorcontrib>L L Bennett, Jr</creatorcontrib><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Web of Science - Science Citation Index Expanded - 1992</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>W B Parker</au><au>S C Shaddix</au><au>P W Allan</au><au>G Arnett</au><au>L M Rose</au><au>W M Shannon</au><au>Y F Shealy</au><au>J A Montgomery</au><au>J A Secrist, 3rd</au><au>L L Bennett, Jr</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Incorporation of the carbocyclic analog of 2'-deoxyguanosine into the DNA of herpes simplex virus and of HEp-2 cells infected with herpes simplex virus</atitle><jtitle>Molecular pharmacology</jtitle><stitle>MOL PHARMACOL</stitle><addtitle>Mol Pharmacol</addtitle><date>1992-02-01</date><risdate>1992</risdate><volume>41</volume><issue>2</issue><spage>245</spage><epage>251</epage><pages>245-251</pages><issn>0026-895X</issn><eissn>1521-0111</eissn><abstract>The carbocyclic analog of 2'-deoxyguanosine (CdG) is active against herpes simplex virus (HSV), human cytomegalovirus, and
human hepatitis-B virus. In order to understand the mechanism of action of this compound against HSV, we have evaluated (a)
the incorporation of [3H]CdG into viral and host DNA in HEp-2 cells infected with HSV and (b) the interaction of the 5'-triphosphate
of CdG (CdG-TP) with the HSV DNA polymerase and human DNA polymerases alpha, beta, and gamma (EC 2.7.7.7). Incubation of HSV-1-infected
HEp-2 cells with [3H]CdG resulted in the incorporation of CdG into both the HSV and the host cell DNA. These results indicated
that CdG-TP was used as a substrate for HSV DNA polymerase and for at least one of the cellular DNA polymerases. Degradation
of both viral and host DNA with micrococcal nuclease and spleen phosphodiesterase indicated that CdG was incorporated primarily
into internal positions in both DNAs. The viral DNA containing CdG sedimented in neutral and alkaline sucrose gradients in
the same way as did viral DNA labeled with [3H]thymidine, indicating that the HSV DNA containing CdG was similar in size to
untreated HSV DNA. CdG-TP was a competitive inhibitor of the incorporation of dGTP into DNA by the HSV DNA polymerase (Ki
of 0.35 microM) and the human DNA polymerase alpha (Ki of 1 microM). CdG-TP was not a potent inhibitor of either DNA polymerase
beta or gamma. Using DNA-sequencing technology, CdG-TP was found to be an efficient substrate for HSV DNA polymerase. Incorporation
of CdG monophosphate (CdG-MP) into the DNA by HSV DNA polymerase did not interfere with subsequent chain extension. These
results suggested that the antiviral activity of CdG was due to its incorporation into the DNA and subsequent disruption of
viral functions. In contrast, CdG-TP was not as good as dGTP as a substrate for DNA synthesis by DNA polymerase alpha, and
incorporation of CdG-MP by DNA polymerase alpha inhibited further DNA chain elongation.</abstract><cop>BALTIMORE</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>1311407</pmid><tpages>7</tpages></addata></record> |
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| ispartof | Molecular pharmacology, 1992-02, Vol.41 (2), p.245-251 |
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| source | Web of Science - Science Citation Index Expanded - 1992<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" />; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Base Sequence Deoxyguanine Nucleotides - metabolism Deoxyguanosine - analogs & derivatives Deoxyguanosine - metabolism DNA, Viral - drug effects DNA, Viral - metabolism Herpes Simplex - metabolism herpes simplex virus 1 Humans Life Sciences & Biomedicine Molecular Sequence Data Nucleic Acid Synthesis Inhibitors Pharmacology & Pharmacy Science & Technology Simplexvirus - metabolism Tritium Viral Proteins - antagonists & inhibitors |
| title | Incorporation of the carbocyclic analog of 2'-deoxyguanosine into the DNA of herpes simplex virus and of HEp-2 cells infected with herpes simplex virus |
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