Ebola virus. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment

Science. 2015 Feb 27;347(6225):995-8. doi: 10.1126/science.1258758.


Ebola virus causes sporadic outbreaks of lethal hemorrhagic fever in humans, but there is no currently approved therapy. Cells take up Ebola virus by macropinocytosis, followed by trafficking through endosomal vesicles. However, few factors controlling endosomal virus movement are known. Here we find that Ebola virus entry into host cells requires the endosomal calcium channels called two-pore channels (TPCs). Disrupting TPC function by gene knockout, small interfering RNAs, or small-molecule inhibitors halted virus trafficking and prevented infection. Tetrandrine, the most potent small molecule that we tested, inhibited infection of human macrophages, the primary target of Ebola virus in vivo, and also showed therapeutic efficacy in mice. Therefore, TPC proteins play a key role in Ebola virus infection and may be effective targets for antiviral therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • BALB 3T3 Cells
  • Benzylisoquinolines / pharmacology
  • Benzylisoquinolines / therapeutic use
  • Calcium Channel Blockers / pharmacology*
  • Calcium Channel Blockers / therapeutic use
  • Calcium Channels / genetics
  • Calcium Channels / physiology*
  • Ebolavirus / drug effects
  • Ebolavirus / physiology*
  • Female
  • Gene Knockout Techniques
  • HeLa Cells
  • Hemorrhagic Fever, Ebola / drug therapy
  • Hemorrhagic Fever, Ebola / therapy*
  • Hemorrhagic Fever, Ebola / virology
  • Humans
  • Macrophages / drug effects
  • Macrophages / virology
  • Mice
  • Molecular Targeted Therapy*
  • NADP / analogs & derivatives
  • NADP / metabolism
  • RNA Interference
  • Signal Transduction
  • Verapamil / pharmacology
  • Verapamil / therapeutic use
  • Virus Internalization / drug effects*


  • Antiviral Agents
  • Benzylisoquinolines
  • Calcium Channel Blockers
  • Calcium Channels
  • TPCN1 protein, human
  • TPCN1 protein, mouse
  • TPCN2 protein, human
  • TPCN2 protein, mouse
  • tetrandrine
  • NADP
  • Verapamil