title: A bifunctional anti-enterovirus compound that inhibits replication and the early stage of enterovirus 71 infection.
abstract: Enviroxime is an anti-enterovirus compound that targets viral protein 3A and/or 3AB and suppresses a replication step of enterovirus by an unknown mechanism. To date, a number of anti-enterovirus compounds that have little structural similarity to enviroxime but induce common resistance mutations in the 3A-encoding region have been identified. The present study identified a novel type of functionally enviroxime-like compound, AN-12-H5. This compound had no structural similarity to enviroxime or to known enviroxime-like compounds, including TTP-8307, GW5074 and Flt3 Inhibitor II. A resistance phenotype of poliovirus (PV) to these compounds was conferred by a major enviroxime-resistance mutation of PV (G5318A, 3A-Ala70Thr), but not by resistance mutations to guanidine hydrochloride and brefeldin A. AN-12-H5 had a common structure with the anti-enterovirus 71 (EV71) compound AN-23-F6. AN-12-H5 and AN-23-F6 inhibited an early stage of EV71 infection after virus binding to the cells. Mutations in capsid proteins (G3112A, VP1-Ala224Thr, and G2396A, VP3-Arg227Lys mutations) were determined as resistant mutations to AN-12-H5 and AN-23-F6 in the early stage of EV71 infection. These results suggest that AN-12-H5 is a bifunctional anti-enterovirus compound that belongs to a novel class of enviroxime-like compounds and targets both a replication step and an early stage of EV71 infection.
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama-shi, Tokyo 208-0011, Japan. minetaro@nih.go.jp
authors.forename: Minetaro
authors.initials: M
authors.lastname: Arita
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takebe
authors.forename: Takaji
authors.initials: T
authors.lastname: Wakita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimizu
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D036022:Capsid Proteins / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D024882:Drug Resistance, Viral; D029821:Enterovirus A, Human / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D015394:Molecular Structure; D020125:Mutation, Missense; D053586:Virus Internalization / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D036022:Capsid Proteins