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

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 a-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.

Development and evaluation of a host-targeted antiviral that abrogates herpes simplex virus replication through modulation of arginine-associated metabolic pathways

“…Not unexpectedly given its novel host-targeted mechanisms of action, peg-ArgI was effective at inhibiting drug resistant HSV-1. Similar to newly identified helicase-primase anti-herpetic drugs (Betz et al, 2002; Kleymann et al, 2002; Weller and Kuchta, 2013), peg-ArgI was superior to acyclovir in its ability to inhibit infectious viral yield, virus-induced cytopathic effect, and viral spread. However, unlike HSVprotein targeting helicase-primase inhibitors, peg-ArgI modulation of host arginine-associated metabolic pathways minimizes the likelihood that viruses could evolve resistance.…”

ATPase activity measurement of DNA replicative helicase from Bacillus stearothermophilus by malachite green method

“…However, at the molar ratio of 1:1, which was supposed to be functional in vivo by structural information [27e29], DnaI showed no inhibition effect on ATPase activity of DnaB (data not shown). This may be explained by an assumption of competition between DnaI and ATP, since ATP hydrolysis was supposed to promote release of DnaC (homologous to DnaI Bst ) from DnaB in E. coli [30,31], conversely, the binding of ATP to DnaB may be inhibited by high concentration of DnaI. However, this assumption requires more work to be done.…”

A short commentary on the review by Weller and Kuchta: the DNA helicase–primase complex as a target for herpes virus infection

“…For anyone new to the field of herpes virus DNA replication may I point you to the perfect introduction to this subject by the doyenne of herpes virus helicase-primase, Sandra K Weller and her co-author, Robert D Kuchta [1]. This is not only an 'expert' opinion in every sense but is also a lucid and readable account that brings a potentially rather dry subject to life.…”