title: Susceptibility of herpes simplex virus isolated from genital herpes lesions to ASP2151, a novel helicase-primase inhibitor.
abstract: ASP2151 (amenamevir) is a helicase-primase inhibitor against herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus. To evaluate the anti-HSV activity of ASP2151, susceptibility testing was performed on viruses isolated from patients participating in a placebo- and valacyclovir-controlled proof-of-concept phase II study for recurrent genital herpes. A total of 156 HSV strains were isolated prior to the dosing of patients, and no preexisting variants with less susceptibility to ASP2151 or acyclovir (ACV) were detected. ASP2151 inhibited HSV-1 and HSV-2 replication with mean 50% effective concentrations (EC(50)s) of 0.043 and 0.069 μM, whereas ACV exhibited mean EC(50)s of 2.1 and 3.2 μM, respectively. Notably, the susceptibilities of HSV isolates to ASP2151 and ACV were not altered after dosing with the antiviral agents. Taken together, these results demonstrate that ASP2151 inhibits the replication of HSV clinical isolates more potently than ACV, and HSV resistant to this novel helicase-primase inhibitor as well as ACV may not easily emerge in short-term treatment for recurrent genital herpes patients.
authors.affiliation: Department of Drug Discovery Research, Astellas Pharma Inc, Tsukuba, Ibaraki, Japan.
authors.forename: Kiyomitsu
authors.initials: K
authors.lastname: Katsumata
authors.forename: Adriana
authors.initials: A
authors.lastname: Weinberg
authors.forename: Koji
authors.initials: K
authors.lastname: Chono
authors.forename: Shoji
authors.initials: S
authors.lastname: Takakura
authors.forename: Toru
authors.initials: T
authors.lastname: Kontani
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D000212:Acyclovir / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D004265:DNA Helicases / Q000037:antagonists & inhibitors*; D019915:DNA Primase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006558:Herpes Genitalis / Q000821:virology*; D006801:Humans; D010069:Oxadiazoles / Q000494:pharmacology*; D018139:Simplexvirus / Q000187:drug effects* / Q000201:enzymology; D014764:Viral Proteins / Q000037:antagonists & inhibitors*
chemical_list: C568714:ASP2151; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D014764:Viral Proteins; D019915:DNA Primase; C062021:helicase-primase, Human herpesvirus 1; D004265:DNA Helicases; D000212:Acyclovir