Varicella-Zoster Virus thymidine kinase and Varicella-Zoster Virus DNA polymerase (VZV TK and VZV DNA Pol)

Varicella-Zoster Virus (VZV) thymidine kinase and DNA polymerase are essential viral enzymes that coordinate the replication of the VZV genome, the causative agent of chickenpox and herpes zoster (shingles) (UniProt P09299, P09275). VZV thymidine kinase, encoded by the ORF36 gene, serves as a critical gatekeeper for antiviral therapy by selectively phosphorylating nucleoside analogs like acyclovir into their monophosphate forms within infected cells (PMID: 11812481). These intermediates are subsequently converted by host cellular kinases into active triphosphate metabolites. These active forms then target the VZV DNA polymerase, encoded by the ORF28 gene, which is responsible for synthesizing new viral DNA strands (StatPearls, PMID: 32644452). By acting as competitive inhibitors and obligate chain terminators, these drugs halt the elongation of the viral DNA, effectively stopping viral replication. This mechanism provides a high therapeutic index because the initial activation step is dependent on the viral kinase rather than host enzymes. However, clinical resistance can develop, most commonly through mutations in the VZV thymidine kinase gene that prevent drug activation (PMID: 15546620).

Other names

HHV-3 thymidine kinaseHHV-3 DNA polymeraseORF36ORF28Varicella-Zoster Virus replication complexHuman herpesvirus 3 thymidine kinaseHuman herpesvirus 3 DNA polymerase

Nucleoside analogs act as prodrugs that are selectively phosphorylated by VZV thymidine kinase into monophosphate forms; these are subsequently converted by cellular kinases into triphosphates which competitively inhibit VZV DNA polymerase and cause DNA chain termination (StatPearls, PMID: 32644452).