Effect of ASP2151, a Herpesvirus Helicase-Primase Inhibitor, in a Guinea Pig Model of Genital Herpes
| Autor: | Yasuaki Shimizu, Kiyomitsu Katsumata, Toru Kontani, Koji Chono, Hiroshi Suzuki, Kenji Sudo |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Herpesvirus 2
Human viruses Drug Evaluation Preclinical Acyclovir amenamevir Pharmaceutical Science Herpesvirus 1 Human Viral Plaque Assay medicine.disease_cause Analytical Chemistry Drug Discovery Oxadiazoles HSV virus diseases Valine Viral Load antiviral Effective dose (pharmacology) Virus Shedding Chemistry (miscellaneous) Area Under Curve Valacyclovir genital herpes Molecular Medicine Female Guinea Pigs ASP2151 guinea pig DNA Primase Antiviral Agents Article lcsh:QD241-441 Viral Proteins lcsh:Organic chemistry medicine Animals Potency Amenamevir Physical and Theoretical Chemistry Viral shedding Herpes Genitalis business.industry Organic Chemistry DNA Helicases Varicella zoster virus Virology Herpes simplex virus Vero cell business |
| Zdroj: | Molecules; Volume 16; Issue 9; Pages: 7210-7223 Molecules Molecules, Vol 16, Iss 9, Pp 7210-7223 (2011) |
| ISSN: | 1420-3049 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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