title: Profile of anti-herpetic action of ASP2151 (amenamevir) as a helicase-primase inhibitor.
abstract: The antiherpetic drugs acyclovir (ACV, valaciclovir) and penciclovir (famciclovir) are phosphorylated by viral thymidine kinase and terminate DNA synthesis. ASP2151 (amenamevir) and foscavir (PFA) directly inhibit viral helicase-primase and DNA polymerase, respectively, and inhibit replication of herpes simplex virus (HSV) and varicella-zoster virus. ACV, ASP2151, and PFA all inhibit HSV with a different mechanism of action and as a consequence, the kinetics of viral DNA accumulation and progeny virus production differ. This study focused on how viral DNA synthesis and its related events in the replication cycle would influence anti-HSV action of ACV, ASP2151, and PFA. ASP2151 suppressed HSV replication more efficiently than ACV at 10 × 50% effective concentration of plaque formation (EC50), when treatments were started 0-24 h after infection. ASP2151 and PFA were more potent than ACV in suppressing viral DNA synthesis and infectious virus production when they were added up to 3 h following infection. The virus replicated in the presence of ACV was compared for the ratios of HSV DNA copy number to infectivity with that without ACV and infectivity of ACV-treated virus was less efficient than that without ACV-treatment. The EC50of infected cells in the time course after infection was preserved in PFA, limited in ASP2151, and much increased for ACV, indicating that viral DNA synthesis had little effect on antiviral action of PFA and ASP2151 but reduced the susceptibility of ACV. ASP2151 showed a preferable profile as an anti-herpetic agent with a better pharmacokinetic profile than ACV.
authors.affiliation: Department of Virology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Misako
authors.initials: M
authors.lastname: Yajima
authors.affiliation: Department of Virology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Department of Microbiology, Faculty of Pharmaceutical Sciences, Hokuriku University, 1-1 Taiyogaoka, Kanazawa 920-1180, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Takemoto
authors.affiliation: Department of Microbiology, Faculty of Pharmaceutical Sciences, Hokuriku University, 1-1 Taiyogaoka, Kanazawa 920-1180, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Daikoku
authors.affiliation: Department of Virology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Department of Virology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Tan
authors.initials: T
authors.lastname: Long
authors.affiliation: Department of Virology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Okuda
authors.affiliation: Department of Virology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address: kshiraki@med.u-toyama.ac.jp.
authors.forename: Kimiyasu
authors.initials: K
authors.lastname: Shiraki
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D002522:Chlorocebus aethiops; D004265:DNA Helicases / Q000037:antagonists & inhibitors*; D019915:DNA Primase / Q000037:antagonists & inhibitors*; D004279:DNA, Viral / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006561:Herpes Simplex / Q000188:drug therapy; D006564:Herpesviridae / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D018258:Herpesvirus 2, Human / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D014645:Herpesvirus 3, Human / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
chemical_list: C568714:ASP2151; D000998:Antiviral Agents; D004279:DNA, Viral; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D019915:DNA Primase; D004265:DNA Helicases
keywords: ASP2151; Amenamevir; Antiviral agents; Helicase-primase inhibitor; Herpes simplex virus