論文

査読有り 本文へのリンクあり
2022年6月16日

A Novel Class of HIV-1 Inhibitors Targeting the Vpr-Induced G2-Arrest in Macrophages by New Yeast- and Cell-Based High-Throughput Screening

Viruses
  • Hirotaka Sato
  • Tomoyuki Murakami
  • Ryosuke Matsuura
  • Masako Abe
  • Seiji Matsuoka
  • Yoko Yashiroda
  • Minoru Yoshida
  • Hirofumi Akari
  • Yosuke Nagasawa
  • Masami Takei
  • Yoko Aida
  • 全て表示

14
6
開始ページ
1321
終了ページ
1321
記述言語
掲載種別
研究論文(学術雑誌)
DOI
10.3390/v14061321
出版者・発行元
MDPI AG

The human immunodeficiency virus type 1 (HIV-1) accessory protein, Vpr, arrests the cell cycle of the G2 phase, and this Vpr-mediated G2 arrest is implicated in an efficient HIV-1 spread in monocyte-derived macrophages. Here, we screened new candidates for Vpr-targeting HIV-1 inhibitors by using fission yeast- and mammalian cell-based high-throughput screening. First, fission yeast strains expressing the HIV-1 Vpr protein were generated and then treated for 48 h with 20 μM of a synthetic library, including 140,000 chemical compounds. We identified 268 compounds that recovered the growth of Vpr-overexpressing yeast. The selected compounds were then tested in mammalian cells, and those displaying high cytotoxicity were excluded from further cell cycle analysis and imaging-based screening. A flow cytometry analysis confirmed that seven compounds recovered from the Vpr-induced G2 arrest. The cell toxicity and inhibitory effect of HIV-1 replication in human monocyte-derived macrophages (MDM) were examined, and three independent structural compounds, VTD227, VTD232, and VTD263, were able to inhibit HIV-1 replication in MDM. Furthermore, we showed that VTD227, but not VTD232 and VTD263, can directly bind to Vpr. Our results indicate that three new compounds and their derivatives represent new drugs targeting HIV-1 replication and can be potentially used in clinics to improve the current antiretroviral therapy.

リンク情報
DOI
https://doi.org/10.3390/v14061321 本文へのリンクあり
URL
https://www.mdpi.com/1999-4915/14/6/1321/pdf
ID情報
  • DOI : 10.3390/v14061321
  • eISSN : 1999-4915

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