Specific recognition of the bicyclic pyrimidine nucleoside analogs, a new class of highly potent and selective inhibitors of varicella-zoster virus (VZV), by the VZV-encoded thymidine kinase.
Recently, an entirely new class of bicyclic nucleoside analogs (BCNAs) was found to display exquisite potency and selectivity as inhibitors of varicella-zoster virus (VZV) replication in cell culture. A striking difference in their ability to convert the BCNAs to their phosphorylated derivatives was observed between the VZV-encoded thymidine kinase (TK) and the very closely related herpes simplex virus type 1 (HSV-1) TK. Whereas VZV TK efficiently phosphorylated the BCNAs, HSV-1 TK was unable to do so. In addition, the thymidylate (dTMP) kinase activity of VZV TK further converted BCNA-5'-MP to BCNA-5'-DP. The BCNAs (or their phosphorylated derivatives) were not a substrate for cytosolic TK, mitochondrial TK, or cytosolic dTMP kinase. Human erythrocyte nucleoside diphosphate (NDP) kinase was unable to phosphorylate the BCNA 5'-diphosphates to BCNA 5'-triphosphates. Under the same experimental conditions, the anti-herpetic (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) derivative was efficiently converted to BVDU-MP and BVDU-DP by both VZV TK and HSV-1 TK and further, into BVDU-TP, by NDP kinase. Our observations may account for the unprecedented specificity of BCNAs as anti-VZV agents.
Sienaert
Rebecca
R
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.
Naesens
Lieve
L
Brancale
Andrea
A
De Clercq
Erik
E
McGuigan
Christopher
C
Balzarini
Jan
J
D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology*; D018259:Herpesvirus 1, Human / Q000201:enzymology; D014645:Herpesvirus 3, Human / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006574:Heterocyclic Compounds, 2-Ring / Q000378:metabolism / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism; D009705:Nucleosides / Q000378:metabolism / Q000494:pharmacology*; D009711:Nucleotides / Q000378:metabolism / Q000494:pharmacology; D009712:Nucleotides, Cyclic / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation; D013937:Thymidine Kinase / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; C446025:Cf 1368; C446026:Cf 1928; D006574:Heterocyclic Compounds, 2-Ring; D009705:Nucleosides; D009711:Nucleotides; D009712:Nucleotides, Cyclic; D013937:Thymidine Kinase; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase