Specific phosphorylation of 5-ethyl-2'-deoxyuridine by herpes simplex virus-infected cells and incorporation into viral DNA.
5-Ethyl-2'-deoxyuridine (EDU) is a potent and selective inhibitor of the replication of herpes simplex virus type 1 (HSV-1) and 2 (HSV-2), which is currently being pursued for the topical treatment of HSV-1 and HSV-2 infections in humans. Using [4-14C]EDU as the radiolabeled analogue of EDU, it was ascertained that, at antivirally active doses, EDU is phosphorylated to a much greater extent by HSV-infected Vero cells than by mock-infected cells. Within the HSV-1-infected cells, EDU was incorporated to a much greater extent into viral DNA than cellular DNA. Using varying doses of EDU, a close correlation was found between the incorporation of EDU into viral DNA, the inhibition of viral DNA synthesis, and the inhibition of virus yield. It is postulated that the selectivity of EDU as an antiviral agent depends on both its preferential phosphorylation by the virus-infected cell and its preferential incorporation into viral DNA. The latter than results in a suppression of viral DNA synthesis and, hence, shutoff of viral progeny formation.
De Clercq
E
E
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Bernaerts
R
R
D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D002472:Cell Transformation, Viral; D004279:DNA, Viral / Q000096:biosynthesis*; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D010766:Phosphorylation; D018139:Simplexvirus / Q000187:drug effects / Q000378:metabolism*; D014709:Vero Cells
D000998:Antiviral Agents; D004279:DNA, Viral; C022811:edoxudin; D003857:Deoxyuridine