ASP2151, a novel helicase-primase inhibitor, possesses antiviral activity against varicella-zoster virus and herpes simplex virus types 1 and 2.

Abstract

OBJECTIVES:

To evaluate and describe the anti-herpesvirus effect of ASP2151, amenamevir, a novel non-nucleoside oxadiazolylphenyl-containing herpesvirus helicase-primase complex inhibitor.

METHODS:

The inhibitory effect of ASP2151 on enzymatic activities associated with a recombinant HSV-1 helicase-primase complex was assessed. To investigate the effect on viral DNA replication, we analysed viral DNA in cells infected with herpesviruses [herpes simplex virus (HSV), varicella-zoster virus (VZV) and human cytomegalovirus]. Sequencing analyses were conducted on an ASP2151-resistant VZV mutant. In vitro and in vivo antiviral activities were evaluated using a plaque reduction assay and an HSV-1-infected zosteriform-spread model in mice.

RESULTS:

ASP2151 inhibited the single-stranded DNA-dependent ATPase, helicase and primase activities associated with the HSV-1 helicase-primase complex. Antiviral assays revealed that ASP2151, unlike other known HSV helicase-primase inhibitors, exerts equipotent activity against VZV, HSV-1 and HSV-2 through prevention of viral DNA replication. Further, the anti-VZV activity of ASP2151 (EC(50), 0.038-0.10 microM) was more potent against all strains tested than that of aciclovir (EC(50), 1.3-27 microM). ASP2151 was also active against aciclovir-resistant VZV. Amino acid substitutions were found in helicase and primase subunits of ASP2151-resistant VZV. In a mouse zosteriform-spread model, ASP2151 was orally active and inhibited disease progression more potently than valaciclovir.

CONCLUSIONS:

ASP2151 is a novel herpes helicase-primase inhibitor that warrants further investigation for the potential treatment of both VZV and HSV infections.

• Authors: Koji Chono, Kiyomitsu Katsumata, Toru Kontani, Masayuki Kobayashi, Kenji Sudo, Tomoyuki Yokota, Kenji Konno, Yasuaki Shimizu, Hiroshi Suzuki
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 65 Issue 8 Pg. 1733-41 (Aug 2010) ISSN: 1460-2091 [Electronic] England
• PMID: 20534624 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Enzyme Inhibitors
• Viral Proteins
• DNA Helicases

Topics

• Animals
• Antiviral Agents (pharmacology, therapeutic use)
• Cytomegalovirus (drug effects)
• DNA Helicases (antagonists & inhibitors)
• DNA Mutational Analysis
• Disease Models, Animal
• Drug Resistance, Viral
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Female
• Herpes Zoster (drug therapy)
• Herpesvirus 1, Human (drug effects)
• Herpesvirus 2, Human (drug effects)
• Herpesvirus 3, Human (drug effects)
• Mice
• Microbial Sensitivity Tests
• Sequence Analysis, DNA
• Viral Plaque Assay
• Viral Proteins (antagonists & inhibitors)
• Virus Replication (drug effects)