RT Journal Article
SR Electronic
T1 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
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 249
OP 254
DO 10.1124/mol.61.2.249
VO 61
IS 2
A1 Sienaert, Rebecca
A1 Naesens, Lieve
A1 Brancale, Andrea
A1 De Clercq, Erik
A1 McGuigan, Christopher
A1 Balzarini, Jan
YR 2002
UL http://molpharm.aspetjournals.org/content/61/2/249.abstract
AB 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.