Varicella-Zoster Virus helicase-primase complex (VZV HP complex)

The Varicella-Zoster Virus (VZV) helicase-primase complex is an essential heterotrimeric enzyme assembly required for the replication of the viral genome [1, 12]. It is composed of three subunits: a DNA helicase (encoded by ORF55), a primase (encoded by ORF6), and a non-catalytic accessory factor (encoded by ORF52) [4, 17, 19]. The complex coordinates multiple enzymatic functions at the replication fork, including the unwinding of double-stranded DNA and the synthesis of short RNA primers required for the initiation of DNA synthesis by the viral DNA polymerase [1, 11]. Unlike traditional nucleoside analogues like acyclovir, which require activation by viral thymidine kinase, inhibitors of this complex such as amenamevir act directly on the replication machinery [5, 9]. This mechanism makes the complex a high-value target for treating infections caused by acyclovir-resistant VZV strains, particularly in immunocompromised patients [2, 7]. Therapeutic intervention targeting this complex is primarily indicated for the treatment of herpes zoster (shingles) to reduce viral shedding and accelerate lesion healing [1, 8]. Furthermore, the non-renal excretory profile of drugs like amenamevir provides a clinical advantage in elderly patients with declining kidney function [9].

Other names

Human alphaherpesvirus 3 helicase-primase complexORF55-ORF6-ORF52 complexVZV H-P complexDNA helicase-primase complexVaricella-Zoster Virus replication complex

Amenamevir inhibits the viral helicase-primase complex by directly binding to the enzyme assembly and blocking its essential activities, including single-stranded DNA-dependent ATPase, helicase (DNA unwinding), and primase (RNA primer synthesis) [1, 7]. This action halts the progression of the viral DNA replication fork, thereby suppressing viral genomic synthesis [1, 9, 11].