title: Effect of ASP2151, a herpesvirus helicase-primase inhibitor, in a guinea pig model of genital herpes.
abstract: ASP2151 is a herpesvirus helicase-primase inhibitor with antiviral activity against varicella zoster virus and herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). Here, we examined the potency and efficacy of ASP2151 against HSV in vitro and in vivo. We found that ASP2151 was more potent in inhibiting the replication of HSV-1 and HSV-2 in Vero cells in the plaque reduction assay and had greater anti-HSV activity in a guinea pig model of genital herpes than did acyclovir and valacyclovir (VACV), respectively. Oral ASP2151 given from the day of infection reduced peak and overall disease scores in a dose-dependent manner, resulting in complete prevention of symptoms at the dose of 30 mg/kg. The 50% effective dose (ED(50)) values for ASP2151 and VACV were 0.37 and 68 mg/kg, respectively, indicating that ASP2151 was 184-fold more potent than VACV. When ASP2151 was administered after the onset of symptoms, the disease course of genital herpes was suppressed more effectively than by VACV, with a significant reduction in disease score observed one day after starting ASP2151 at 30 mg/kg, whereas the therapeutic effect of VACV was only evident three days after treatment at the highest dose tested (300 mg/kg). This indicated that ASP2151 possesses a faster onset of action and wider therapeutic time window than VACV. Further, virus shedding from the genital mucosa was significantly reduced with ASP2151 at 10 and 30 mg/kg but not with VACV, even at 300 mg/kg. Taken together, our present findings demonstrated the superior potency and efficacy of ASP2151 against HSV.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc, 21, Miyukigaoka, Tsukuba, Ibaraki, Japan. kiyomitsu.katsumata@jp.astellas.com
authors.forename: Kiyomitsu
authors.initials: K
authors.lastname: Katsumata
authors.forename: Koji
authors.initials: K
authors.lastname: Chono
authors.forename: Kenji
authors.initials: K
authors.lastname: Sudo
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Toru
authors.initials: T
authors.lastname: Kontani
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D000212:Acyclovir / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019540:Area Under Curve; D004265:DNA Helicases / Q000037:antagonists & inhibitors*; D019915:DNA Primase / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical; D005260:Female; D006168:Guinea Pigs; D006558:Herpes Genitalis / Q000188:drug therapy* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D018258:Herpesvirus 2, Human / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D010069:Oxadiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D000077483:Valacyclovir; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D019562:Viral Load / Q000187:drug effects; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000037:antagonists & inhibitors*; D017201:Virus Shedding / Q000187:drug effects
chemical_list: C568714:ASP2151; D000998:Antiviral Agents; D010069:Oxadiazoles; D014764:Viral Proteins; D019915:DNA Primase; C062021:helicase-primase, Human herpesvirus 1; D004265:DNA Helicases; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir