title: Antiviral drug resistance and helicase-primase inhibitors of herpes simplex virus.
abstract: A new class of chemical inhibitors has been discovered that interferes with the process of herpesvirus DNA replication. To date, the majority of useful herpesvirus antivirals are nucleoside analogues that block herpesvirus DNA replication by targeting the DNA polymerase. The new helicase-primase inhibitors (HPI) target a different enzyme complex that is also essential for herpesvirus DNA replication. This review will place the HPI in the context of previous work on the nucleoside analogues. Several promising highly potent HPI will be described with a particular focus on the identification of drug-resistance mutations. Several HPI have good pharmacological profiles and are now at the outset of phase II clinical trials. Provided there are no safety issues to stop their progress, this new class of compound will be a major advance in the herpesvirus antiviral field. Furthermore, HPI are likely to have a major impact on the therapy and prevention of herpes simplex virus and varicella zoster in both immunocompetent and immunocompromised patients alone or in combination with current nucleoside analogues. The possibility of acquired drug-resistance to HPI will then become an issue of great practical importance.
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB30ES, United Kingdom. hjf10@cam.ac.uk
authors.forename: Hugh J
authors.initials: HJ
authors.lastname: Field
authors.forename: Subhajit
authors.initials: S
authors.lastname: Biswas
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D004265:DNA Helicases / Q000037:antagonists & inhibitors*; D019915:DNA Primase / Q000037:antagonists & inhibitors*; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006558:Herpes Genitalis / Q000188:drug therapy / Q000201:enzymology; D006561:Herpes Simplex / Q000188:drug therapy / Q000201:enzymology; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000201:enzymology; D018258:Herpesvirus 2, Human / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D014764:Viral Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D014764:Viral Proteins; D019915:DNA Primase; C062021:helicase-primase, Human herpesvirus 1; D004265:DNA Helicases