title: Synergistic activity of amenamevir (ASP2151) with nucleoside analogs against herpes simplex virus types 1 and 2 and varicella-zoster virus.
abstract: ASP2151 (amenamevir) is a helicase-primase complex inhibitor with antiviral activity against herpes simplex virus HSV-1, HSV-2, and varicella-zoster virus (VZV). To assess combination therapy of ASP2151 with existing antiherpes agents against HSV-1, HSV-2, and VZV, we conducted in vitro and in vivo studies of two-drug combinations. The combination activity effect of ASP2151 with nucleoside analogs acyclovir (ACV), penciclovir (PCV), or vidarabine (VDB) was tested via plaque-reduction assay and MTS assay, and the data were analyzed using isobolograms and response surface modeling. In vivo combination therapy of ASP2151 with valaciclovir (VACV) was studied in an HSV-1-infected zosteriform spread mouse model. The antiviral activity of ASP2151 combined with ACV and PCV against ACV-susceptible HSV-1, HSV-2, and VZV showed a statistically significant synergistic effect (P<0.05). ASP2151 with VDB was observed to have additive effects against ACV-susceptible HSV-2 and synergistic effects against VZV. In the mouse model of zosteriform spread, the inhibition of disease progression via combination therapy was more potent than that of either drugs as monotherapy (P<0.05). These results indicate that the combination therapies of ASP2151 with ACV and PCV have synergistic antiherpes effects against HSV and VZV infections and may be feasible in case of severe disease, such as herpes encephalitis or in patients with immunosuppression.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Chono
authors.forename: Kiyomitsu
authors.initials: K
authors.lastname: Katsumata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Kimiyasu
authors.initials: K
authors.lastname: Shiraki
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006562:Herpes Zoster / Q000188:drug therapy; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D018258:Herpesvirus 2, Human / Q000187:drug effects*; D014645:Herpesvirus 3, Human / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D009705:Nucleosides / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology*; D016896:Treatment Outcome; D014709:Vero Cells; D010948:Viral Plaque Assay
chemical_list: C568714:ASP2151; D009705:Nucleosides; D010069:Oxadiazoles