(E)-5-(2-bromovinyl)uridine requires phosphorylation by the herpes simplex virus (type 1)-induced thymidine kinase to express its antiviral activity.
(E)-5-(2-Bromovinyl)uridine (BVUrd), the riboside counterpart of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdUrd), effected a dose-dependent inhibition of viral progeny formation and viral DNA synthesis in herpes simplex virus type 1 (HSV-1, strain KOS)-infected human (E6SM) diploid fibroblast cells. BVUrd was directly phosphorylated in HSV-1-infected cells, presumably by the virus-encoded thymidine kinase (TK), since (i) BVUrd was not phosphorylated by extracts of cells infected with a HSV-1 strain deficient in TK expression and (ii) the phosphorylation was inhibited by a polyclonal anti-HSV-1 antibody. Within the HSV-1-infected cells, BVUrd was incorporated into the viral DNA as BVdUMP (BVdUrd 5'-monophosphate). This incorporation may account for the antiviral action of BVUrd, and implies that, following its initial phosphorylation by the viral TK, BVUrd is converted to its 2'-deoxy counterpart, most likely at the 5'-diphosphate level (BVUDP----BVdUDP).
Bernaerts
R
R
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Desgranges
C
C
De Clercq
E
E
D000998:Antiviral Agents / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004251:DNA Transposable Elements; D004279:DNA, Viral / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D010766:Phosphorylation; D018139:Simplexvirus / Q000201:enzymology*; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism
D000998:Antiviral Agents; D004251:DNA Transposable Elements; D004279:DNA, Viral; C020235:brivudine; D013937:Thymidine Kinase; D001973:Bromodeoxyuridine