The helicase-primase complex as a target for effective herpesvirus antivirals

Herpes simplex virus and varicella-zoster virus have been treated for more that half a century using nucleoside analogues. However, there is still an unmet clinical need for improved herpes antivirals. The successful compounds, acyclovir; penciclovir and their orally bioavailable prodrugs valaciclovir and famciclovir, ultimately block virus replication by inhibiting virus-specific DNA-polymerase. The helicase-primase (HP) complex offers a distinctly different target for specific inhibition of virus DNA synthesis. This review describes the synthetic programmes that have already led to two HP-inhibitors (HPI) that have commenced clinical trials in man. One of these (known as AIC 316) continues in clinical development to date. The specificity of HPI is reflected by the ability to select drug-resistant mutants. The role of HP-antiviral resistance will be considered and how the study of cross--resistance among mutants already shows subtle differences between compounds in this respect. The impact of resistance on the drug development in the clinic will also be considered. Finally, herpesvirus latency remains as the most important barrier to a therapeutic cure. Whether or not helicase primase inhibitors alone or in combination with nucleoside analogues can impact on this elusive goal remains to be seen.