title: Inhibition of CRM1-mediated nuclear export of influenza A nucleoprotein and nuclear export protein as a novel target for antiviral drug development.
abstract: An anti-influenza compound, DP2392-E10 based on inhibition of the nuclear export function of the viral nucleoprotein-nuclear export signal 3 (NP-NES3) domain was successfully identified by our previous high-throughput screening system. Here, we demonstrated that DP2392-E10 exerts its antiviral effect by inhibiting replication of a broad range of influenza A subtypes. In regard to the molecular mechanism, we revealed that DP2392-E10 inhibits nuclear export of both viral NP and nuclear export protein (NEP). More specifically, in vitro pull-down assays revealed that DP2392-E10 directly binds cellular CRM1, which mediates nuclear export of NP and NEP. In silico docking suggested that DP2392-E10 binds at a region close to the HEAT9 and HEAT10 domains of CRM1. Together, these results indicate that the CRM1-mediated nuclear export function of influenza virus represents a new potential target for antiviral drug development, and also provide a core structure for a novel class of inhibitors that target this function.
authors.affiliation: Viral Infectious Disease Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Nopporn
authors.initials: N
authors.lastname: Chutiwitoonchai
authors.affiliation: Viral Infectious Disease Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Mano
authors.affiliation: Viral Infectious Disease Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Michinori
authors.initials: M
authors.lastname: Kakisaka
authors.affiliation: Viral Infectious Disease Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Sato
authors.affiliation: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Yasumitsu
authors.initials: Y
authors.lastname: Kondoh
authors.affiliation: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
authors.affiliation: Laboratory of Viral Genomics, Pathogen Genomics Center, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo 208-0011, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Kotani
authors.affiliation: Laboratory of Viral Genomics, Pathogen Genomics Center, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo 208-0011, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Yokoyama
authors.affiliation: Laboratory of Viral Genomics, Pathogen Genomics Center, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo 208-0011, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Sato
authors.affiliation: Viral Infectious Disease Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: aida@riken.jp.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Aida
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism / Q000821:virology; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000378:metabolism*; D007251:Influenza, Human / Q000378:metabolism* / Q000821:virology; D028884:Karyopherins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009698:Nucleoproteins / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000097606:Exportin 1 Protein
chemical_list: D000998:Antiviral Agents; D028884:Karyopherins; D009698:Nucleoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein
keywords: Chromosome region maintenance 1; Influenza A virus; Nuclear export protein; Nuclear export signal; Nucleoprotein