Synthesis of a Vpr-Binding derivative for use as a novel HIV-1 Inhibitor

Kyoji Hagiwara, Hideki Ishii, Tomoyuki Murakami, Shin Nosuke Takeshima, Nopporn Chutiwitoonchai, Eiichi N. Kodama, Kumi Kawaji, Yasumitsu Kondoh, Kaori Honda, Hiroyuki Osada, Yasuko Tsunetsugu-Yokota, Masaaki Suzuki, Yoko Aida

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1 Citation (Scopus)

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 Vprdependent 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.

Original languageEnglish
Article numbere0145573
JournalPloS one
Volume10
Issue number12
DOIs
Publication statusPublished - 2015 Dec 1

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Hagiwara, K., Ishii, H., Murakami, T., Takeshima, S. N., Chutiwitoonchai, N., Kodama, E. N., Kawaji, K., Kondoh, Y., Honda, K., Osada, H., Tsunetsugu-Yokota, Y., Suzuki, M., & Aida, Y. (2015). Synthesis of a Vpr-Binding derivative for use as a novel HIV-1 Inhibitor. PloS one, 10(12), [e0145573]. https://doi.org/10.1371/journal.pone.0145573