Novel anti-flavivirus drugs targeting the nucleolar distribution of core protein

Virology. 2020 Feb;541:41-51. doi: 10.1016/j.virol.2019.11.015. Epub 2019 Nov 29.

Abstract

The risk of infectious diseases caused by Flavivirus is increasing globally. Here, we developed a novel high-throughput screening (HTS) system to evaluate the inhibitory effects of compounds targeting the nuclear localization of the flavivirus core protein. We screened 4000 compounds based on their ability to inhibit the nuclear localization of the core protein, and identified over 20 compounds including inhibitors for cyclin dependent kinase and glycogen synthase kinase. The efficacy of the identified compounds to suppress viral growth was validated in a cell-based infection system. Remarkably, the nucleolus morphology was affected by the treatment with the compounds, suggesting that the nucleolus function is critical for viral propagation. The present HTS system provides a useful strategy for the identification of antivirals against flavivirus by targeting the nucleolar localization of the core protein.

Keywords: Core protein; Flavivirus; High-throughput screening; Nuclear transport; Nucleolus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Antiviral Agents / pharmacology*
  • Cell Nucleolus / drug effects*
  • Cell Nucleolus / metabolism
  • Cell Nucleolus / pathology
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Flavivirus / drug effects*
  • Flavivirus / physiology
  • HEK293 Cells
  • High-Throughput Screening Assays
  • Humans
  • Viral Core Proteins / metabolism*

Substances

  • Antiviral Agents
  • Viral Core Proteins
  • Cyclin-Dependent Kinases