title: Thiopurines inhibit bovine viral diarrhea virus production in a thiopurine methyltransferase-dependent manner.
abstract: The family Flaviviridae comprises positive-strand RNA viral pathogens of humans and livestock with few treatment options. We have previously shown that azathioprine (AZA) has in vitro 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 S-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.
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, 1550 Linden Drive, Madison, WI, USA.
authors.forename: Spencer
authors.initials: S
authors.lastname: Hoover
authors.affiliation: Department of Medicine, University of Wisconsin, Madison, W. S. Middleton Memorial Veteran's Hospital, Madison, WI, USA.|Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, 1550 Linden Drive, Madison, WI, USA.
authors.forename: Rob
authors.initials: R
authors.lastname: Striker
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology; D001379:Azathioprine / Q000378:metabolism / Q000494:pharmacology*; D001912:Bovine Virus Diarrhea-Mucosal Disease / Q000188:drug therapy* / Q000821:virology; D002417:Cattle; D002460:Cell Line; D001908:Diarrhea Viruses, Bovine Viral / Q000187:drug effects* / Q000502:physiology; D008778:Methylthioinosine / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D008780:Methyltransferases / Q000378:metabolism / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D008778:Methylthioinosine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D000241:Adenosine; D001379:Azathioprine