Sienaert, R., Naesens, L., Brancale, Andrea  ORCID: https://orcid.org/0000-0002-9728-3419, De Clercq, E., McGuigan, Christopher ORCID: https://orcid.org/0000-0001-8409-710X and Balzarini, J.
2002.
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.
Molecular Pharmacology
61
(2)
, pp. 249-254.
10.1124/mol.61.2.249
|
Abstract
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.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Schools > Pharmacy Research Institutes & Centres > Systems Immunity Research Institute (SIURI) |
| Subjects: | R Medicine > RS Pharmacy and materia medica |
| ISSN: | 0026895X |
| Last Modified: | 05 Jan 2024 05:59 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/7481 |
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