Herpes simplex virus helicase-primase complex (HSV helicase-primase) (HSV helicase-primase)

The Herpes simplex virus (HSV) helicase-primase complex is a heterotrimeric enzyme essential for viral DNA replication, composed of the UL5 helicase, UL52 primase, and UL8 accessory protein subunits (UniProt: P10235, P10238, P10237). This complex is responsible for unwinding double-stranded DNA and synthesizing RNA primers on the lagging strand, activities that are critical for the progression of the viral replication fork (PubMed: 11961554). As a therapeutic target, it is highly attractive because it is essential for both HSV-1 and HSV-2 and does not have a direct human counterpart, minimizing off-target effects. Unlike nucleoside analogs such as acyclovir, inhibitors of this complex like pritelivir and amenamevir do not require phosphorylation by viral thymidine kinase to be active, allowing them to treat acyclovir-resistant strains (PubMed: 24428469). These drugs function by binding to the complex and preventing the dissociation of the enzyme from the DNA, effectively stalling the replication machinery (PubMed: 22158877). Clinical studies have demonstrated that targeting this complex significantly reduces viral shedding and the duration of symptoms in patients with genital herpes (PubMed: 24428469).

Other names

UL5/UL8/UL52 complexHSV-1 helicase-primaseHSV-2 helicase-primaseHerpes simplex virus DNA helicase-primase complex

Helicase-primase inhibitors (HPIs) bind to the UL5/UL52/UL8 complex, stabilizing the interaction between the enzyme and the DNA template. This prevents the unwinding of the DNA duplex and the synthesis of RNA primers, which are necessary for lagging-strand DNA synthesis, thereby halting viral genome replication (PubMed: 11961554, PubMed: 22158877).