title: Synthesis of a Vpr-Binding Derivative for Use as a Novel HIV-1 Inhibitor.
abstract: The emergence of multidrug-resistant viruses compromises the efficacy of anti-human immunodeficiency virus type 1 (HIV-1) therapy and limits treatment options. Therefore, new targets that can be used to develop novel antiviral agents need to be identified. We previously identified a potential parent compound, hematoxylin, which suppresses the nuclear import of HIV-1 via the Vpr-importin α interaction and inhibits HIV-1 replication in a Vpr-dependent manner by blocking nuclear import of the pre-integration complex. However, it was unstable. Here, we synthesized a stable derivative of hematoxylin that bound specifically and stably to Vpr and inhibited HIV-1 replication in macrophages. Furthermore, like hematoxylin, the derivative inhibited nuclear import of Vpr in an in vitro nuclear import assay, but had no effect on Vpr-induced G2/M phase cell cycle arrest or caspase activity. Interestingly, this derivative bound strongly to amino acid residues 54-74 within the C-terminal α-helical domain (αH3) of Vpr. These residues are highly conserved among different HIV strains, indicating that this region is a potential target for drug-resistant HIV-1 infection. Thus, we succeeded in developing a stable hematoxylin derivative that bound directly to Vpr, suggesting that specific inhibitors of the interaction between cells and viral accessory proteins may provide a new strategy for the treatment of HIV-1 infection.
authors.affiliation: Viral Infectious Diseases Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Kyoji
authors.initials: K
authors.lastname: Hagiwara
authors.affiliation: Molecular Imaging Medicinal Chemistry Laboratory, RIKEN Center for Molecular Imaging Science, 6-7-3 Minatoshima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ishii
authors.affiliation: Viral Infectious Diseases Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Murakami
authors.affiliation: Viral Infectious Diseases Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Shin-nosuke
authors.initials: SN
authors.lastname: Takeshima
authors.affiliation: Viral Infectious Diseases Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Nopporn
authors.initials: N
authors.lastname: Chutiwitoonchai
authors.affiliation: Division of Miyagi Community Health Promotion, Tohoku University Graduate School of Medicine, 2-1 Seiryocho, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Eiichi N
authors.initials: EN
authors.lastname: Kodama
authors.affiliation: Division of Miyagi Community Health Promotion, Tohoku University Graduate School of Medicine, 2-1 Seiryocho, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Kawaji
authors.affiliation: Chemical Biology Research Group, RIKEN CSRS, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Yasumitsu
authors.initials: Y
authors.lastname: Kondoh
authors.affiliation: Chemical Biology Research Group, RIKEN CSRS, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Honda
authors.affiliation: Chemical Biology Research Group, RIKEN CSRS, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
authors.affiliation: Department of Frontier Biosciences, Department of Immunology, National Institute of Infectious Diseases, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Tsunetsugu-Yokota
authors.affiliation: Molecular Imaging Medicinal Chemistry Laboratory, RIKEN Center for Molecular Imaging Science, 6-7-3 Minatoshima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Viral Infectious Diseases Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Aida
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002478:Cells, Cultured; D015658:HIV Infections / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006416:Hematoxylin / Q000737:chemistry*; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000821:virology; D014779:Virus Replication / Q000187:drug effects*; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D019380:Anti-HIV Agents; D054325:vpr Gene Products, Human Immunodeficiency Virus; D006416:Hematoxylin