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: 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
• Journal: PloS one (PLoS One) Vol. 10 Issue 12 Pg. e0145573 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26701275 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• vpr Gene Products, Human Immunodeficiency Virus
• Hematoxylin

Topics

• Anti-HIV Agents (chemical synthesis, pharmacology)
• Cells, Cultured
• HIV Infections (prevention & control, virology)
• HIV-1 (drug effects)
• Hematoxylin (chemistry)
• Humans
• Macrophages (drug effects, virology)
• Virus Replication (drug effects)
• vpr Gene Products, Human Immunodeficiency Virus (metabolism)