title: Efficacy of ASP2151, a helicase-primase inhibitor, against thymidine kinase-deficient herpes simplex virus type 2 infection in vitro and in vivo.
abstract: ASP2151 was developed as a novel inhibitor of herpes simplex virus (HSV) and varicella-zoster virus helicase-primase. The anti-HSV activity of ASP2151 toward a clinical HSV isolate with acyclovir (ACV)-resistant/thymidine kinase (TK)-deficiency was characterized in vitro and in vivo using a plaque reduction assay and the ear pinna infection in mice. The IC(50) ranged from 0.018 to 0.024 μg/ml, indicating the susceptibility of TK-deficient HSV-2 was similar to that of wild-type HSV-2 strains. Anti-HSV activity of ASP2151 in vivo was evaluated in mice infected with wild-type HSV-2 and TK-deficient HSV-2. ASP2151 significantly reduced the copy numbers of wild-type HSV-2 and TK-deficient HSV-2 at the inoculation ear pinna, while valacyclovir significantly reduced the copy number of wild type HSV-2 but not that of TK-deficient HSV-2 in the inoculated ear pinna. Thus, ASP 2151 showed therapeutic efficacy in mice infected with both wild-type and TK-deficient HSV-2. In conclusion, ASP2151 is a promising novel herpes helicase-primase inhibitor that indicates the feasibility of ASP2151 for clinical application for the treatment of HSV infections, including ACV-resistant/TK-deficient HSV infection.
authors.affiliation: Department of Virology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Himaki
authors.affiliation: Department of Virology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Masui
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Miyukigaoka 21, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Chono
authors.affiliation: Department of Virology, University of Toyama, 2630 Sugitani, Toyama 930-0194, 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: Masaya
authors.initials: M
authors.lastname: Takemoto
authors.affiliation: Department of Virology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Bo
authors.initials: B
authors.lastname: Haixia
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: Drug Discovery Research, Astellas Pharma Inc., Miyukigaoka 21, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
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 / Q000008:administration & dosage* / Q000737:chemistry; D002460:Cell Line; D004265:DNA Helicases / Q000037:antagonists & inhibitors*; D019915:DNA Primase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry; D005260:Female; D006561:Herpes Simplex / Q000188:drug therapy / Q000821:virology*; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010069:Oxadiazoles / Q000008:administration & dosage* / Q000737:chemistry; D013937:Thymidine Kinase / Q000172:deficiency* / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C568714:ASP2151; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D014764:Viral Proteins; D013937:Thymidine Kinase; D019915:DNA Primase; D004265:DNA Helicases