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Review
. 2013 Oct;17(10):1119-32.
doi: 10.1517/14728222.2013.827663. Epub 2013 Aug 12.

The DNA helicase-primase complex as a target for herpes viral infection

Sandra K Weller  1 , Robert D Kuchta
Affiliations
Review

The DNA helicase-primase complex as a target for herpes viral infection

Sandra K Weller et al. Expert Opin Ther Targets. 2013 Oct.

Abstract

Introduction: The Herpesviridae are responsible for debilitating acute and chronic infections, and some members of this family are associated with human cancers. Conventional anti-herpesviral therapy targets the viral DNA polymerase and has been extremely successful; however, the emergence of drug-resistant virus strains, especially in neonates and immunocompromised patients, underscores the need for continued development of anti-herpes drugs. In this article, we explore an alternative target for antiviral therapy, the HSV helicase/primase complex.

Areas covered: This review addresses the current state of knowledge of HSV DNA replication and the important roles played by the herpesvirus helicase- primase complex. In the last 10 years several helicase/primase inhibitors (HPIs) have been described, and in this article, we discuss and contrast these new agents with established inhibitors.

Expert opinion: The outstanding safety profile of existing nucleoside analogues for α-herpesvirus infection make the development of new therapeutic agents a challenge. Currently used nucleoside analogues exhibit few side effects and have low occurrence of clinically relevant resistance. For HCMV, however, existing drugs have significant toxicity issues and the frequency of drug resistance is high, and no antiviral therapies are available for EBV and KSHV. The development of new anti-herpesvirus drugs is thus well worth pursuing especially for immunocompromised patients and those who develop drug-resistant infections. Although the HPIs are promising, limitations to their development into a successful drug strategy remain.

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Conflict of interest statement

The authors state no conflict of interest and have received no payment in preparation of this manuscript.

Figures

Figure 1
Figure 1. Domain structure of the three subunits of the HSV helicase/primase (UL5, UL8 and UL52)
The conserved motifs of UL5 are shown as seven black boxes shared within superfamily 1 members. Two conserved UL52 domains are shown: the LVFDID catalytic domain (608 – 630) and putative zinc binding domain at the C-terminus (residues 998 – 1028). UL8 is a 751 aa protein with no known functional motifs.
Figure 2
Figure 2. HSV replication fork and model for model for coordinated leading- and lagging-strand DNA synthesis
A. An HSV-1 replication fork would be expected to contain the helicase–primase complex (UL5/UL52/UL8) at the fork: UL5 would be expected to unwind duplex DNA ahead of the fork, and UL52 would be expected to lay down RNA primers that the two-subunit DNA polymerase (UL30/UL42) extends. The HSV-1 Pol also carries out leading-strand synthesis. ICP8 (UL29, SSB) presumably binds to ssDNA generated during HSV DNA synthesis. B. Coupled leading- and lagging-strand synthesis was recently reconstituted in vitro and requires HSV polymerase, helicase–primase and ICP8 [74]. In this model, coupled leading-and lagging-strand DNA synthesis requires two heterotrimers of helicase/primase and two molecules of the DNA polymerase. The leading- and lagging-strand polymerase molecules are proposed to communicate with each other through interactions between UL30 and the helicase–primase. A replication loop is formed in the lagging-strand to align it with the leading-strand. The lagging-strand DNA polymerase initiates Okazaki fragment synthesis using RNA primers (hatched bars).
Figure 3
Figure 3. Structures of HPIs
T157602 (1,3-thiazol-2-amine); BAY 57-1293 (AIC316 or Pritelivir) N-methyl-N-(4-methyl-5-sulfamoyl-1, 3-thiazol-2-yl)-2-[4-(pyridin-2-yl)phenyl]acetamide); ASP2151 (Amenamevir) - N-(2,6-dimethylphenyl)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)etrahydro-2-H-thiopyran-4-carboxamide 1,1-dioxide; BILS 22 BS N-(2-{[4-(2-amino-1,3-thiazol-4-yl)phenyl]amino}-2-oxoethyl)-N-benzylbenzamide.
Figure 4
Figure 4
A. UL5 amino acid substitutions in HSV-1 mutants resistant to HPIs. Several HPI-resistant mutations have been mapped to the UL5 gene. The amino acid substitutions are shown for mutants resistant to T157602, BAY 57-1293, BILS 22BS or ASP2151 [104,107,108,119,122]. B. UL52 Amino acid substitutions in HSV mutants resistant to HPIs. Arg367His was found in a ASP2151-resistant mutant [122] and A899T was found in a BAY 57-1293-resistant mutant [121]
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