{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T08:55:19Z","timestamp":1768812919456,"version":"3.49.0"},"reference-count":40,"publisher":"Microbiology Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,4,1]]},"abstract":"<jats:p>The family <jats:italic>Flaviviridae<\/jats:italic> comprises positive-strand RNA viral pathogens of humans and livestock with few treatment options. We have previously shown that azathioprine (AZA) has <jats:italic>in vitro<\/jats:italic> activity against bovine viral diarrhea virus (BVDV). While the mechanism of inhibition is unknown, AZA and related thiopurine nucleoside analogues have been used as immunosuppressants for decades and both AZA metabolites and cellular genes involved in AZA metabolism have been extensively characterized. Here, we show that only certain riboside metabolites have antiviral activity and identify the most potent known antiviral AZA metabolite as 6-methylmercaptopurine riboside (6MMPr). The antiviral activity of 6MMPr is antagonized by adenosine, and is specific to BVDV and not to the related yellow fever virus. An essential step in the conversion of AZA to 6MMPr is the addition of a methyl group onto the sulfur atom attached to position six of the purine ring. Intracellularly, the methyl group is added by thiopurine methyltransferase (TPMT), an <jats:italic>S<\/jats:italic>-adenosyl methionine-dependent methyltransferase. Either chemically bypassing or inhibiting TPMT modulates antiviral activity of AZA metabolites. TPMT exists in several variants with varying levels of activity and since 6MMPr is a potent antiviral, the antiviral activity of AZA may be modulated by host genetics.<\/jats:p>","DOI":"10.1099\/vir.0.83381-0","type":"journal-article","created":{"date-parts":[[2008,3,14]],"date-time":"2008-03-14T06:38:13Z","timestamp":1205476693000},"page":"1000-1009","source":"Crossref","is-referenced-by-count":15,"title":["Thiopurines inhibit bovine viral diarrhea virus production in a thiopurine methyltransferase-dependent manner"],"prefix":"10.1099","volume":"89","author":[{"given":"Spencer","family":"Hoover","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, 1550 Linden Drive, Madison, WI, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rob","family":"Striker","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin, Madison, W. S. Middleton Memorial Veteran's Hospital, Madison, WI, USA"},{"name":"Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, 1550 Linden Drive, Madison, WI, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"345","reference":[{"key":"R1","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1016\/j.transproceed.2005.02.103","article-title":"Retrospective analysis of the impact of immunosuppression on the course of recurrent hepatitis C after liver transplantation","volume":"37","author":"Bahr","year":"2005","journal-title":"Transplant Proc"},{"key":"R2","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1006\/abbi.1993.1311","article-title":"Characterization of the cellular reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT): subcellular localization, substrate dependence, and involvement of mitochondrial electron transport in MTT reduction","volume":"303","author":"Berridge","year":"1993","journal-title":"Arch Biochem Biophys"},{"key":"R3","doi-asserted-by":"crossref","first-page":"3482","DOI":"10.1128\/JVI.76.7.3482-3492.2002","article-title":"Structural analysis of the hepatitis C virus RNA polymerase in complex with ribonucleotides","volume":"76","author":"Bressanelli","year":"2002","journal-title":"J Virol"},{"key":"R4","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/35065653","article-title":"A mechanism for initiating RNA-dependent RNA polymerization","volume":"410","author":"Butcher","year":"2001","journal-title":"Nature"},{"key":"R5","doi-asserted-by":"crossref","first-page":"4425","DOI":"10.1073\/pnas.0400660101","article-title":"The structure of the RNA-dependent RNA polymerase from bovine viral diarrhea virus establishes the role of GTP in de novo initiation","volume":"101","author":"Choi","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R6","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1124\/mol.62.1.102","article-title":"The effect of thiopurine methyltransferase expression on sensitivity to thiopurine drugs","volume":"62","author":"Coulthard","year":"2002","journal-title":"Mol Pharmacol"},{"key":"R7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jmb.2004.01.030","article-title":"Excision of incorporated nucleotide analogue chain-terminators can diminish their inhibitory effects on viral RNA-dependent RNA polymerases","volume":"337","author":"D'Abramo","year":"2004","journal-title":"J Mol Biol"},{"key":"R8","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1093\/clinchem\/48.1.61","article-title":"HPLC determination of thiopurine nucleosides and nucleotides in vivo in lymphoblasts following mercaptopurine therapy","volume":"48","author":"Dervieux","year":"2002","journal-title":"Clin Chem"},{"key":"R9","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.1373\/clinchem.2005.050831","article-title":"Liquid chromatography-tandem mass spectrometry analysis of erythrocyte thiopurine nucleotides and effect of thiopurine methyltransferase gene variants on these metabolites in patients receiving azathioprine\/6-mercaptopurine therapy","volume":"51","author":"Dervieux","year":"2005","journal-title":"Clin Chem"},{"key":"R10","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/BF01119794","article-title":"Nobel Lecture. The purine path to chemotherapy","volume":"9","author":"Elion","year":"1989","journal-title":"Biosci Rep"},{"key":"R11","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.bbrc.2006.02.134","article-title":"Involvement of the concentrative nucleoside transporter 3 and equilibrative nucleoside transporter 2 in the resistance of T-lymphoblastic cell lines to thiopurines","volume":"343","author":"Fotoohi","year":"2006a","journal-title":"Biochem Biophys Res Commun"},{"key":"R12","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1016\/j.bcp.2006.06.019","article-title":"Molecular mechanisms underlying the enhanced sensitivity of thiopurine-resistant T-lymphoblastic cell lines to methyl mercaptopurineriboside","volume":"72","author":"Fotoohi","year":"2006b","journal-title":"Biochem Pharmacol"},{"key":"R13","first-page":"399","article-title":"Choice of azathioprine or 6-mercaptopurine dose based on thiopurine methyltransferase (TPMT) activity to avoid myelosuppression. A prospective study","volume":"53","author":"Gisbert","year":"2006","journal-title":"Hepatogastroenterology"},{"key":"R14","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1006\/viro.2002.1487","article-title":"Quasispecies, error catastrophe, and the antiviral activity of ribavirin","volume":"298","author":"Graci","year":"2002","journal-title":"Virology"},{"key":"R15","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0378-1135(98)00262-4","article-title":"Epidemiological features and economical importance of bovine virus diarrhoea virus (BVDV) infections","volume":"64","author":"Houe","year":"1999","journal-title":"Vet Microbiol"},{"key":"R16","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1053\/jlts.2001.27803","article-title":"Histological recurrence and progression of hepatitis C after orthotopic liver transplantation: influence of immunosuppressive regimens","volume":"7","author":"Hunt","year":"2001","journal-title":"Liver Transpl"},{"key":"R17","doi-asserted-by":"crossref","first-page":"2997","DOI":"10.1128\/JVI.76.6.2997-3006.2002","article-title":"Selectable subgenomic and genome-length dicistronic RNAs derived from an infectious molecular clone of the HCV-N strain of hepatitis C virus replicate efficiently in cultured Huh7 cells","volume":"76","author":"Ikeda","year":"2002","journal-title":"J Virol"},{"key":"R18","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.virol.2004.10.034","article-title":"Construction and applications of yellow fever virus replicons","volume":"331","author":"Jones","year":"2005","journal-title":"Virology"},{"key":"R19","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1021\/jm049029u","article-title":"Design, synthesis, and antiviral activity of adenosine 5\u2032-phosphonate analogues as chain terminators against hepatitis C virus","volume":"48","author":"Koh","year":"2005","journal-title":"J Med Chem"},{"key":"R20","first-page":"651","article-title":"Comparison of the effects of 6-thio- and 6-methylthiopurine ribonucleoside cyclic monophosphates with their corresponding nucleosides on the growth of rat hepatoma cells","volume":"37","author":"Koontz","year":"1977","journal-title":"Cancer Res"},{"key":"R21","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.intimp.2004.09.010","article-title":"Impact of mycophenolate mofetil versus azathioprine on early recurrence of hepatitis C after liver transplantation","volume":"5","author":"Kornberg","year":"2005","journal-title":"Int Immunopharmacol"},{"key":"R22","first-page":"35","article-title":"Global surveillance and control of hepatitis C. Report of a WHO Consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium","volume":"6","author":"Lavanchy","year":"1999","journal-title":"J Viral Hepat"},{"key":"R23","first-page":"802","article-title":"Consequences of 6-thioguanine incorporation into DNA on polymerase, ligase, and endonuclease reactions","volume":"42","author":"Ling","year":"1992","journal-title":"Mol Pharmacol"},{"key":"R24","doi-asserted-by":"crossref","first-page":"S98","DOI":"10.1038\/nm1144","article-title":"Emerging flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses","volume":"10","author":"Mackenzie","year":"2004","journal-title":"Nat Med"},{"key":"R25","doi-asserted-by":"crossref","first-page":"574","DOI":"10.3181\/00379727-98-24111","article-title":"Established kidney cell lines of normal adult bovine and ovine origin","volume":"98","author":"Madin","year":"1958","journal-title":"Proc Soc Exp Biol Med"},{"key":"R26","doi-asserted-by":"crossref","first-page":"4737","DOI":"10.1128\/JVI.72.6.4737-4745.1998","article-title":"Infectious bovine viral diarrhea virus (strain NADL) RNA from stable cDNA clones: a cellular insert determines NS3 production and viral cytopathogenicity","volume":"72","author":"Mendez","year":"1998","journal-title":"J Virol"},{"key":"R27","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/S0009-9236(97)90152-1","article-title":"Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms","volume":"62","author":"Otterness","year":"1997","journal-title":"Clin Pharmacol Ther"},{"key":"R28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0166-3542(03)00088-3","article-title":"Mechanisms of antiviral treatment efficacy and failure in chronic hepatitis C","volume":"59","author":"Pawlotsky","year":"2003","journal-title":"Antiviral Res"},{"key":"R29","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1002\/lt.20344","article-title":"Immunosuppression and donor age with respect to severity of HCV recurrence after liver transplantation","volume":"11","author":"Samonakis","year":"2005","journal-title":"Liver Transpl"},{"key":"R30","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1097\/01.TP.0000114610.40412.C6","article-title":"Effect of antimetabolite immunosuppressants on Flaviviridae , including hepatitis C virus","volume":"77","author":"Stangl","year":"2004","journal-title":"Transplantation"},{"key":"R31","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1042\/bj3040163","article-title":"Decrease in S -adenosylmethionine synthesis by 6-mercaptopurine and methylmercaptopurine ribonucleoside in Molt F4 human malignant lymphoblasts","volume":"304","author":"Stet","year":"1994","journal-title":"Biochem J"},{"key":"R32","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1111\/j.1365-2125.1995.tb04478.x","article-title":"Sulphasalazine inhibition of thiopurine methyltransferase: possible mechanism for interaction with 6-mercaptopurine and azathioprine","volume":"39","author":"Szumlanski","year":"1995","journal-title":"Br J Clin Pharmacol"},{"key":"R33","doi-asserted-by":"crossref","first-page":"6444","DOI":"10.1073\/pnas.94.12.6444","article-title":"Enhanced proteolysis of thiopurine S -methyltransferase (TPMT) encoded by mutant alleles in humans ( TPMT*3A , TPMT*2 ): mechanisms for the genetic polymorphism of TPMT activity","volume":"94","author":"Tai","year":"1997","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R34","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S0168-1702(00)00176-3","article-title":"Bovine viral diarrhea virus induced apoptosis correlates with increased intracellular viral RNA accumulation","volume":"69","author":"Vassilev","year":"2000","journal-title":"Virus Res"},{"key":"R35","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/0925-4439(93)90110-M","article-title":"The importance of methylthio-IMP for methylmercaptopurine ribonucleoside (Me-MPR) cytotoxicity in Molt F4 human malignant T-lymphoblasts","author":"Vogt","year":"1993","journal-title":"Biochim Biophys Acta"},{"key":"R36","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1038\/sj.onc.1209372","article-title":"Thiopurine S -methyltransferase pharmacogenetics: insights, challenges and future directions","volume":"25","author":"Wang","year":"2006","journal-title":"Oncogene"},{"key":"R37","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1097\/00008571-200309000-00004","article-title":"Thiopurine S -methyltransferase pharmacogenetics: chaperone protein association and allozyme degradation","volume":"13","author":"Wang","year":"2003","journal-title":"Pharmacogenetics"},{"key":"R38","first-page":"471","article-title":"Thiopurine methyltransferase. Aromatic thiol substrates and inhibition by benzoic acid derivatives","volume":"24","author":"Woodson","year":"1983","journal-title":"Mol Pharmacol"},{"key":"R39","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1006\/viro.2002.1652","article-title":"Subgenomic hepatitis C virus replicons inducing expression of a secreted enzymatic reporter protein","volume":"304","author":"Yi","year":"2002","journal-title":"Virology"},{"key":"R40","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1128\/JVI.74.4.2017-2022.2000","article-title":"De novo initiation of RNA synthesis by hepatitis C virus nonstructural protein 5B polymerase","volume":"74","author":"Zhong","year":"2000","journal-title":"J Virol"}],"container-title":["Journal of General Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.microbiologyresearch.org\/content\/journal\/jgv\/10.1099\/vir.0.83381-0?crawler=true","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T12:29:09Z","timestamp":1604492949000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.microbiologyresearch.org\/content\/journal\/jgv\/10.1099\/vir.0.83381-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,4,1]]},"references-count":40,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2008,4,1]]}},"URL":"https:\/\/doi.org\/10.1099\/vir.0.83381-0","relation":{},"ISSN":["0022-1317","1465-2099"],"issn-type":[{"value":"0022-1317","type":"print"},{"value":"1465-2099","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,4,1]]}}}