Synthesis of a Vpr-Binding Derivative for Use as a Novel HIV-1 Inhibitor.
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...
Main Authors: | , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2015-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC4689350?pdf=render |
id |
doaj-ba129c7472764fcab634ab5e88aab3dc |
---|---|
record_format |
Article |
spelling |
doaj-ba129c7472764fcab634ab5e88aab3dc2020-11-24T22:05:45ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-011012e014557310.1371/journal.pone.0145573Synthesis of a Vpr-Binding Derivative for Use as a Novel HIV-1 Inhibitor.Kyoji HagiwaraHideki IshiiTomoyuki MurakamiShin-nosuke TakeshimaNopporn ChutiwitoonchaiEiichi N KodamaKumi KawajiYasumitsu KondohKaori HondaHiroyuki OsadaYasuko Tsunetsugu-YokotaMasaaki SuzukiYoko AidaThe 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.http://europepmc.org/articles/PMC4689350?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Synthesis of a Vpr-Binding Derivative for Use as a Novel HIV-1 Inhibitor. PLoS ONE |
author_facet |
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 |
author_sort |
Kyoji Hagiwara |
title |
Synthesis of a Vpr-Binding Derivative for Use as a Novel HIV-1 Inhibitor. |
title_short |
Synthesis of a Vpr-Binding Derivative for Use as a Novel HIV-1 Inhibitor. |
title_full |
Synthesis of a Vpr-Binding Derivative for Use as a Novel HIV-1 Inhibitor. |
title_fullStr |
Synthesis of a Vpr-Binding Derivative for Use as a Novel HIV-1 Inhibitor. |
title_full_unstemmed |
Synthesis of a Vpr-Binding Derivative for Use as a Novel HIV-1 Inhibitor. |
title_sort |
synthesis of a vpr-binding derivative for use as a novel hiv-1 inhibitor. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2015-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC4689350?pdf=render |
work_keys_str_mv |
AT kyojihagiwara synthesisofavprbindingderivativeforuseasanovelhiv1inhibitor AT hidekiishii synthesisofavprbindingderivativeforuseasanovelhiv1inhibitor AT tomoyukimurakami synthesisofavprbindingderivativeforuseasanovelhiv1inhibitor AT shinnosuketakeshima synthesisofavprbindingderivativeforuseasanovelhiv1inhibitor AT noppornchutiwitoonchai synthesisofavprbindingderivativeforuseasanovelhiv1inhibitor AT eiichinkodama synthesisofavprbindingderivativeforuseasanovelhiv1inhibitor AT kumikawaji synthesisofavprbindingderivativeforuseasanovelhiv1inhibitor AT yasumitsukondoh synthesisofavprbindingderivativeforuseasanovelhiv1inhibitor AT kaorihonda synthesisofavprbindingderivativeforuseasanovelhiv1inhibitor AT hiroyukiosada synthesisofavprbindingderivativeforuseasanovelhiv1inhibitor AT yasukotsunetsuguyokota synthesisofavprbindingderivativeforuseasanovelhiv1inhibitor AT masaakisuzuki synthesisofavprbindingderivativeforuseasanovelhiv1inhibitor AT yokoaida synthesisofavprbindingderivativeforuseasanovelhiv1inhibitor |
_version_ |
1725824823854104576 |