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A Diacylglycerol Kinase Inhibitor, R-59-022, Blocks Filovirus Internalization in Host Cells

Corina M Stewart1,2,3, Stephanie S Dorion4, Marie A F Ottenbrite5

  • 1Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada. cwark095@uottawa.ca.

Viruses
|March 6, 2019
PubMed

Insights

A diacylglycerol kinase inhibitor, R-59-022, effectively blocks Ebola virus (EBOV) entry into cells by inhibiting macropinocytosis. This finding offers a potential therapeutic strategy against filoviral infections.

Area of Science:

  • Virology
  • Cell Biology
  • Drug Discovery

Background:

  • Filoviruses, including Ebola virus (EBOV) and Marburg virus, cause severe hemorrhagic fevers.
  • Filovirus entry into host cells requires internalization and delivery to intracellular vesicles containing cathepsin proteases and Niemann-Pick C1.
  • EBOV entry is known to involve glycoprotein (GP)-dependent macropinocytosis, but the precise molecular mechanisms remain unclear.

Purpose of the Study:

  • To investigate the molecular events governing filovirus internalization.
  • To identify potential therapeutic targets for filoviral infections.

Main Methods:

  • Utilized the diacylglycerol kinase inhibitor R-59-022 to study EBOV entry.
  • Examined the effect of R-59-022 on viral particle internalization via macropinocytosis in Vero cells and macrophages.
  • Tested R-59-022 against various pathogenic filovirus GPs and replicative EBOV.

Main Results:

  • R-59-022 effectively inhibited EBOV glycoprotein (GP)-mediated entry into Vero cells and macrophages.
  • The inhibitor blocked an early step in viral entry, specifically the internalization of viral particles through macropinocytosis.
  • R-59-022 demonstrated efficacy against a range of filovirus GPs and inhibited the replication of Ebola virus.

Conclusions:

  • Diacylglycerol kinase inhibition by R-59-022 represents a novel strategy to block filovirus entry.
  • R-59-022 can serve as a valuable research tool for studying filovirus macropinocytosis.
  • This inhibitor shows promise as a potential starting point for developing broad-spectrum antiviral therapeutics against filoviruses.
Keywords:
Ebola virusMarburg virusdiacylglycerol kinasefilovirusesmacropinocytosisviral entry

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