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

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

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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:	Pharmacy 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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