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: Kiyomitsu Katsumata, Koji Chono, Kenji Sudo, Yasuaki Shimizu, Toru Kontani, Hiroshi Suzuki
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 16 Issue 9 Pg. 7210-23 (Aug 25 2011) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 21869749 (Publication Type: Journal Article)

Chemical References

• ASP2151
• Antiviral Agents
• Oxadiazoles
• Viral Proteins
• DNA Primase
• helicase-primase, Human herpesvirus 1
• DNA Helicases
• Valine
• Valacyclovir
• Acyclovir

Topics

• Acyclovir (analogs & derivatives, pharmacology)
• Animals
• Antiviral Agents (pharmacology, therapeutic use)
• Area Under Curve
• DNA Helicases (antagonists & inhibitors)
• DNA Primase (antagonists & inhibitors)
• Drug Evaluation, Preclinical
• Female
• Guinea Pigs
• Herpes Genitalis (drug therapy, virology)
• Herpesvirus 1, Human (drug effects, enzymology, growth & development)
• Herpesvirus 2, Human (drug effects, enzymology, growth & development)
• Oxadiazoles (pharmacology, therapeutic use)
• Valacyclovir
• Valine (analogs & derivatives, pharmacology)
• Viral Load (drug effects)
• Viral Plaque Assay
• Viral Proteins (antagonists & inhibitors)
• Virus Shedding (drug effects)