ASP2151, a novel helicase-primase inhibitor, possesses antiviral activity against varicella-zoster virus and herpes simplex virus types 1 and 2.
OBJECTIVE
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.
Drug Discovery Research, Astellas Pharma Inc., Tokyo, Japan.
Koji
K
Chono
Kiyomitsu
K
Katsumata
Toru
T
Kontani
Masayuki
M
Kobayashi
Kenji
K
Sudo
Tomoyuki
T
Yokota
Kenji
K
Konno
Yasuaki
Y
Shimizu
Hiroshi
H
Suzuki
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003587:Cytomegalovirus / Q000187:drug effects; D004265:DNA Helicases / Q000037:antagonists & inhibitors*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006562:Herpes Zoster / Q000188:drug therapy; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D018258:Herpesvirus 2, Human / Q000187:drug effects*; D014645:Herpesvirus 3, Human / Q000187:drug effects*; D051379:Mice; D008826:Microbial Sensitivity Tests; D017422:Sequence Analysis, DNA; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000037:antagonists & inhibitors; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D014764:Viral Proteins; D004265:DNA Helicases