Characterization of virus strains resistant to the herpes virus helicase–primase inhibitor ASP2151 (Amenamevir)

• Published in: Biochemical pharmacology Vol. 84; no. 4; pp. 459 - 467
• Main Authors: Chono, Koji, Katsumata, Kiyomitsu, Kontani, Toru, Shiraki, Kimiyasu, Suzuki, Hiroshi
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 15.08.2012
• Subjects: Amenamevir; Amino Acid Sequence; Amino Acid Substitution; amino acids; Animals; Antiviral Agents - pharmacology; ASP2151; Cells, Cultured; Cercopithecus aethiops; DNA Helicases - antagonists & inhibitors; DNA Helicases - genetics; DNA Primase - antagonists & inhibitors; DNA Primase - genetics; Drug Resistance, Viral; Female; genes; Helicase–primase inhibitor; herpes simplex; Herpes Simplex - virology; Herpes simplex viruses; Herpesvirus 1, Human - drug effects; Herpesvirus 1, Human - enzymology; Herpesvirus 1, Human - pathogenicity; Herpesvirus 2, Human - drug effects; Herpesvirus 2, Human - enzymology; Herpesvirus 2, Human - genetics; Human herpesvirus 3; Humans; Mice; Mice, Hairless; Molecular Sequence Data; mutants; Mutation; Oxadiazoles - pharmacology; pathogenicity; pharmacology; sequence analysis; Viral Plaque Assay; Viral Proteins - antagonists & inhibitors; Viral Proteins - genetics; virus replication; viruses; HPI; HSV-1; VZV; ACV; Helicase–primase inhibitor; HHV; TK; Herpes simplex viruses; Amenamevir; HSV-2; ASP2151
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2012.05.020

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.