Inactivity of the bicyclic pyrimidine nucleoside analogues against simian varicella virus (SVV) does not correlate with their substrate activity for SVV-encoded thymidine kinase.
Simian varicella virus (SVV) and human varicella-zoster virus (VZV) are closely related viruses that share many structural and functional properties. 5-Substituted 2'-deoxyuridine derivatives (e.g., BVDU, BVaraU) and acyclic guanine nucleoside derivatives (i.e., ACV and GCV) show comparable antiviral efficacy against VZV and SVV in cell culture. In contrast, the novel bicyclic nucleoside analogues (BCNAs) are exquisitely inhibitory to VZV (EC50 in the lower nanomolar range) but completely inactive against SVV. The VZV-encoded thymidine kinase (TK) appeared to be essential for BCNA activation (phosphorylation) and anti-VZV activity. Also SVV TK is able to recognize the BCNAs as substrate, although with a different structure-affinity relationship. Thus, viral TK-catalyzed phosphorylation is necessary but not sufficient for the BCNAs to display antiviral activity. Our data suggest that the eventual target of the BCNAs against VZV is either absent in SVV or, alternatively, is insensitive for the (phosphorylated) BCNAs.
Sienaert
R
R
Rega Institute for Medical Research, Katholieke, Universiteit Leuven, B-3000 Leuven, Belgium.
Andrei
G
G
Snoeck
R
R
De Clercq
E
E
McGuigan
C
C
Balzarini
J
J
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000166:cytology / Q000201:enzymology / Q000821:virology; D011741:Pyrimidine Nucleosides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013223:Statistics as Topic; D013379:Substrate Specificity; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D018140:Varicellovirus / Q000187:drug effects* / Q000201:enzymology*
D000998:Antiviral Agents; D001643:Bridged Bicyclo Compounds; D004791:Enzyme Inhibitors; D011741:Pyrimidine Nucleosides; D011994:Recombinant Proteins; D013937:Thymidine Kinase