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

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 (EC50, 0.038–0.10 µM) was more potent against all strains tested than that of aciclovir (EC50, 1.3–27 µM). 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.