Distinct thymidine kinases encoded by cowpox virus and herpes simplex virus contribute significantly to the differential antiviral activity of nucleoside analogs
Orthopoxviruses and herpesviruses are both large enveloped DNA viruses, yet these virus families exhibit very different susceptibilities to antiviral drugs. We investigated the activation of nucleoside analogs by the types I and II thymidine kinase (TK) homologs expressed by herpes simplex virus typ...
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description | Orthopoxviruses and herpesviruses are both large enveloped DNA viruses, yet these virus families exhibit very different susceptibilities to antiviral drugs. We investigated the activation of nucleoside analogs by the types I and II thymidine kinase (TK) homologs expressed by herpes simplex virus type 1 (HSV-1) and cowpox virus (CV). Antiviral activity against TK
− and TK
+ strains of HSV-1 and CV was determined, and the ratio of the EC
50 values was used as a measurement of TK dependence. As to HSV-1, most of the selected compounds were markedly less effective against the TK
− strains, suggesting that this enzyme was required for the activation of these nucleoside analogs. This differs from the results for CV where only idoxuridine and bromodeoxyuridine appeared to be activated, putatively by the type II TK expressed by this virus. These data confirm that the type II TK encoded by CV exhibits a more limited substrate specificity than the type I TK encoded by HSV-1. These data suggest that the inefficient activation of nucleoside analogs by the orthopoxvirus TK significantly limits their activity. Additional screening against orthopoxviruses will be required to identify nucleoside analogs that are efficiently activated by their type II TK. |
doi_str_mv | 10.1016/j.antiviral.2006.01.013 |
format | Article |
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− and TK
+ strains of HSV-1 and CV was determined, and the ratio of the EC
50 values was used as a measurement of TK dependence. As to HSV-1, most of the selected compounds were markedly less effective against the TK
− strains, suggesting that this enzyme was required for the activation of these nucleoside analogs. This differs from the results for CV where only idoxuridine and bromodeoxyuridine appeared to be activated, putatively by the type II TK expressed by this virus. These data confirm that the type II TK encoded by CV exhibits a more limited substrate specificity than the type I TK encoded by HSV-1. These data suggest that the inefficient activation of nucleoside analogs by the orthopoxvirus TK significantly limits their activity. Additional screening against orthopoxviruses will be required to identify nucleoside analogs that are efficiently activated by their type II TK.</description><identifier>ISSN: 0166-3542</identifier><identifier>EISSN: 1872-9096</identifier><identifier>DOI: 10.1016/j.antiviral.2006.01.013</identifier><identifier>PMID: 16530858</identifier><identifier>CODEN: ARSRDR</identifier><language>eng</language><publisher>Amsterdam: Elsevier B.V</publisher><subject>Amino Acid Sequence ; Animals ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Antiviral Agents - pharmacokinetics ; Antiviral Agents - pharmacology ; beta-Galactosidase - metabolism ; Biological and medical sciences ; Biotransformation ; Cercopithecus aethiops ; Cowpox virus ; Cowpox virus - enzymology ; Cowpox virus - genetics ; Fibroblasts ; Herpes simplex virus 1 ; Herpesviruses ; Humans ; Medical sciences ; Molecular Sequence Data ; Nucleotides - pharmacokinetics ; Nucleotides - pharmacology ; Orthopoxvirus ; Orthopoxviruses ; Pharmacology. Drug treatments ; Phylogeny ; Sequence Alignment ; Simplexvirus - enzymology ; Simplexvirus - genetics ; Substrate Specificity ; Thymidine ; Thymidine Kinase - genetics ; Thymidine Kinase - metabolism ; Vero Cells ; Viral Plaque Assay</subject><ispartof>Antiviral research, 2006-08, Vol.71 (1), p.1-6</ispartof><rights>2006 Elsevier B.V.</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c430t-f727f7779146a664b96fc34d83a74e3a8be9a8f605b8b49ee1ad794ecd137e413</citedby><cites>FETCH-LOGICAL-c430t-f727f7779146a664b96fc34d83a74e3a8be9a8f605b8b49ee1ad794ecd137e413</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.antiviral.2006.01.013$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17891639$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16530858$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Prichard, Mark N.</creatorcontrib><creatorcontrib>Williams, Angela D.</creatorcontrib><creatorcontrib>Keith, Kathy A.</creatorcontrib><creatorcontrib>Harden, Emma A.</creatorcontrib><creatorcontrib>Kern, Earl R.</creatorcontrib><title>Distinct thymidine kinases encoded by cowpox virus and herpes simplex virus contribute significantly to the differential antiviral activity of nucleoside analogs</title><title>Antiviral research</title><addtitle>Antiviral Res</addtitle><description>Orthopoxviruses and herpesviruses are both large enveloped DNA viruses, yet these virus families exhibit very different susceptibilities to antiviral drugs. We investigated the activation of nucleoside analogs by the types I and II thymidine kinase (TK) homologs expressed by herpes simplex virus type 1 (HSV-1) and cowpox virus (CV). Antiviral activity against TK
− and TK
+ strains of HSV-1 and CV was determined, and the ratio of the EC
50 values was used as a measurement of TK dependence. As to HSV-1, most of the selected compounds were markedly less effective against the TK
− strains, suggesting that this enzyme was required for the activation of these nucleoside analogs. This differs from the results for CV where only idoxuridine and bromodeoxyuridine appeared to be activated, putatively by the type II TK expressed by this virus. These data confirm that the type II TK encoded by CV exhibits a more limited substrate specificity than the type I TK encoded by HSV-1. These data suggest that the inefficient activation of nucleoside analogs by the orthopoxvirus TK significantly limits their activity. Additional screening against orthopoxviruses will be required to identify nucleoside analogs that are efficiently activated by their type II TK.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - pharmacokinetics</subject><subject>Antiviral Agents - pharmacology</subject><subject>beta-Galactosidase - metabolism</subject><subject>Biological and medical sciences</subject><subject>Biotransformation</subject><subject>Cercopithecus aethiops</subject><subject>Cowpox virus</subject><subject>Cowpox virus - enzymology</subject><subject>Cowpox virus - genetics</subject><subject>Fibroblasts</subject><subject>Herpes simplex virus 1</subject><subject>Herpesviruses</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Molecular Sequence Data</subject><subject>Nucleotides - pharmacokinetics</subject><subject>Nucleotides - pharmacology</subject><subject>Orthopoxvirus</subject><subject>Orthopoxviruses</subject><subject>Pharmacology. Drug treatments</subject><subject>Phylogeny</subject><subject>Sequence Alignment</subject><subject>Simplexvirus - enzymology</subject><subject>Simplexvirus - genetics</subject><subject>Substrate Specificity</subject><subject>Thymidine</subject><subject>Thymidine Kinase - genetics</subject><subject>Thymidine Kinase - metabolism</subject><subject>Vero Cells</subject><subject>Viral Plaque Assay</subject><issn>0166-3542</issn><issn>1872-9096</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1v1DAQhiMEokvhL4Av9JbFjhN_HKvyKVXiAmfLscetl8RebKeQn9N_ile7tMdKI9nSPDPzzrxN847gLcGEfdhtdSj-zic9bTuM2RaTGvRZsyGCd63Ekj1vNpVkLR367qx5lfMOV5BL8bI5I2ygWAxi09x_9Ln4YAoqt-vsrQ-AfvmgM2QEwUQLFo0rMvHPPv5FdeCSkQ4W3ULaVyT7eT_B_4SJoSQ_LgVq4iZ4502VOa2oxNoekPXOQYKqXE_oYQGkzeFXVhQdCouZIGZvoQJ6ijf5dfPC6SnDm9N73vz8_OnH1df2-vuXb1eX163pKS6t4x13nHNJeqYZ60fJnKG9FVTzHqgWI0gtHMPDKMZeAhBtuezBWEI59ISeNxfHvvsUfy-Qi5p9NjBNOkBcsmJiqNej_EmQSNGxrsMV5EfQpJhzAqf2yc86rYpgdbBR7dTDFdTBRoVJDVor355GLOMM9rHu5FsF3p8AnY2eXNLB-PzIcSEJo7Jyl0cO6uXuPCSVja--gvUJTFE2-ifF_AMS-8Uj</recordid><startdate>20060801</startdate><enddate>20060801</enddate><creator>Prichard, Mark N.</creator><creator>Williams, Angela D.</creator><creator>Keith, Kathy A.</creator><creator>Harden, Emma A.</creator><creator>Kern, Earl R.</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20060801</creationdate><title>Distinct thymidine kinases encoded by cowpox virus and herpes simplex virus contribute significantly to the differential antiviral activity of nucleoside analogs</title><author>Prichard, Mark N. ; Williams, Angela D. ; Keith, Kathy A. ; Harden, Emma A. ; Kern, Earl R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c430t-f727f7779146a664b96fc34d83a74e3a8be9a8f605b8b49ee1ad794ecd137e413</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Antiviral Agents - pharmacokinetics</topic><topic>Antiviral Agents - pharmacology</topic><topic>beta-Galactosidase - metabolism</topic><topic>Biological and medical sciences</topic><topic>Biotransformation</topic><topic>Cercopithecus aethiops</topic><topic>Cowpox virus</topic><topic>Cowpox virus - enzymology</topic><topic>Cowpox virus - genetics</topic><topic>Fibroblasts</topic><topic>Herpes simplex virus 1</topic><topic>Herpesviruses</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Molecular Sequence Data</topic><topic>Nucleotides - pharmacokinetics</topic><topic>Nucleotides - pharmacology</topic><topic>Orthopoxvirus</topic><topic>Orthopoxviruses</topic><topic>Pharmacology. Drug treatments</topic><topic>Phylogeny</topic><topic>Sequence Alignment</topic><topic>Simplexvirus - enzymology</topic><topic>Simplexvirus - genetics</topic><topic>Substrate Specificity</topic><topic>Thymidine</topic><topic>Thymidine Kinase - genetics</topic><topic>Thymidine Kinase - metabolism</topic><topic>Vero Cells</topic><topic>Viral Plaque Assay</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Prichard, Mark N.</creatorcontrib><creatorcontrib>Williams, Angela D.</creatorcontrib><creatorcontrib>Keith, Kathy A.</creatorcontrib><creatorcontrib>Harden, Emma A.</creatorcontrib><creatorcontrib>Kern, Earl R.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Antiviral research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Prichard, Mark N.</au><au>Williams, Angela D.</au><au>Keith, Kathy A.</au><au>Harden, Emma A.</au><au>Kern, Earl R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Distinct thymidine kinases encoded by cowpox virus and herpes simplex virus contribute significantly to the differential antiviral activity of nucleoside analogs</atitle><jtitle>Antiviral research</jtitle><addtitle>Antiviral Res</addtitle><date>2006-08-01</date><risdate>2006</risdate><volume>71</volume><issue>1</issue><spage>1</spage><epage>6</epage><pages>1-6</pages><issn>0166-3542</issn><eissn>1872-9096</eissn><coden>ARSRDR</coden><abstract>Orthopoxviruses and herpesviruses are both large enveloped DNA viruses, yet these virus families exhibit very different susceptibilities to antiviral drugs. We investigated the activation of nucleoside analogs by the types I and II thymidine kinase (TK) homologs expressed by herpes simplex virus type 1 (HSV-1) and cowpox virus (CV). Antiviral activity against TK
− and TK
+ strains of HSV-1 and CV was determined, and the ratio of the EC
50 values was used as a measurement of TK dependence. As to HSV-1, most of the selected compounds were markedly less effective against the TK
− strains, suggesting that this enzyme was required for the activation of these nucleoside analogs. This differs from the results for CV where only idoxuridine and bromodeoxyuridine appeared to be activated, putatively by the type II TK expressed by this virus. These data confirm that the type II TK encoded by CV exhibits a more limited substrate specificity than the type I TK encoded by HSV-1. These data suggest that the inefficient activation of nucleoside analogs by the orthopoxvirus TK significantly limits their activity. Additional screening against orthopoxviruses will be required to identify nucleoside analogs that are efficiently activated by their type II TK.</abstract><cop>Amsterdam</cop><pub>Elsevier B.V</pub><pmid>16530858</pmid><doi>10.1016/j.antiviral.2006.01.013</doi><tpages>6</tpages></addata></record> |
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subjects | Amino Acid Sequence Animals Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - pharmacokinetics Antiviral Agents - pharmacology beta-Galactosidase - metabolism Biological and medical sciences Biotransformation Cercopithecus aethiops Cowpox virus Cowpox virus - enzymology Cowpox virus - genetics Fibroblasts Herpes simplex virus 1 Herpesviruses Humans Medical sciences Molecular Sequence Data Nucleotides - pharmacokinetics Nucleotides - pharmacology Orthopoxvirus Orthopoxviruses Pharmacology. Drug treatments Phylogeny Sequence Alignment Simplexvirus - enzymology Simplexvirus - genetics Substrate Specificity Thymidine Thymidine Kinase - genetics Thymidine Kinase - metabolism Vero Cells Viral Plaque Assay |
title | Distinct thymidine kinases encoded by cowpox virus and herpes simplex virus contribute significantly to the differential antiviral activity of nucleoside analogs |
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