Characterization of virus strains resistant to the herpes virus helicase-primase inhibitor ASP2151 (Amenamevir).
ASP2151 is an antiherpes agent targeting the helicase-primase complex of herpes simplex virus (HSV)-1, HSV-2, and varicella-zoster virus (VZV). We characterized the ASP2151-resistant HSV-1 and HSV-2 variants or mutants based on findings from sequencing analysis, growth, pathogenicity, and susceptibility testing, identifying several single base-pair substitutions resulting in amino acid changes in the helicase and primase subunit of ASP2151-resistant mutants. Amino acid alterations in the helicase subunit were clustered near helicase motif IV in the UL5 helicase gene of both HSV-1 and HSV-2, while the primase subunit substitution associated with reduced susceptibility, R367H, was found in ASP2151-resistant HSV-1 mutants. However, while susceptibility in the ASP2151-resistant HSV mutants to existing antiherpes agents was equivalent to that in wild-type HSV strains, ASP2151-resistant HSV mutants showed attenuated in vitro growth capability and in vivo pathogenicity compared with the parent strains. Taken together, our present findings demonstrated that important amino acid substitutions associated with reduced susceptibilities of HSV-1 and HSV-2 to ASP2151 exist in both the helicase and primase subunits of the helicase-primase complex, and that mutations in this complex against ASP2151 might confer defects in viral replication and pathogenicity.
Drug Discovery Research, Astellas Pharma Inc., Miyukigaoka 21, Tsukuba, Ibaraki 305-8585, Japan.
Koji
K
Chono
Kiyomitsu
K
Katsumata
Toru
T
Kontani
Kimiyasu
K
Shiraki
Hiroshi
H
Suzuki
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004265:DNA Helicases / Q000037:antagonists & inhibitors* / Q000235:genetics; D019915:DNA Primase / Q000037:antagonists & inhibitors* / Q000235:genetics; D024882:Drug Resistance, Viral; D005260:Female; D006561:Herpes Simplex / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D051379:Mice; D008812:Mice, Hairless; D008969:Molecular Sequence Data; D009154:Mutation; D010069:Oxadiazoles / Q000494:pharmacology*; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics
C568714:ASP2151; D000998:Antiviral Agents; D010069:Oxadiazoles; D014764:Viral Proteins; D019915:DNA Primase; C062021:helicase-primase, Human herpesvirus 1; D004265:DNA Helicases