FDA-approved selective estrogen receptor modulators inhibit Ebola virus infection

Sci Transl Med. 2013 Jun 19;5(190):190ra79. doi: 10.1126/scitranslmed.3005471.

Abstract

Ebola viruses remain a substantial threat to both civilian and military populations as bioweapons, during sporadic outbreaks, and from the possibility of accidental importation from endemic regions by infected individuals. Currently, no approved therapeutics exist to treat or prevent infection by Ebola viruses. Therefore, we performed an in vitro screen of Food and Drug Administration (FDA)- and ex-US-approved drugs and selected molecular probes to identify drugs with antiviral activity against the type species Zaire ebolavirus (EBOV). From this screen, we identified a set of selective estrogen receptor modulators (SERMs), including clomiphene and toremifene, which act as potent inhibitors of EBOV infection. Anti-EBOV activity was confirmed for both of these SERMs in an in vivo mouse infection model. This anti-EBOV activity occurred even in the absence of detectable estrogen receptor expression, and both SERMs inhibited virus entry after internalization, suggesting that clomiphene and toremifene are not working through classical pathways associated with the estrogen receptor. Instead, the response appeared to be an off-target effect where the compounds interfere with a step late in viral entry and likely affect the triggering of fusion. These data support the screening of readily available approved drugs to identify therapeutics for the Ebola viruses and other infectious diseases. The SERM compounds described in this report are an immediately actionable class of approved drugs that can be repurposed for treatment of filovirus infections.

Publication types

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

MeSH terms

  • Animals
  • Cathepsins / metabolism
  • Chlorocebus aethiops
  • Clomiphene / pharmacology
  • Clomiphene / therapeutic use
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Approval*
  • Ebolavirus / drug effects
  • Ebolavirus / physiology*
  • Endosomes / drug effects
  • Endosomes / metabolism
  • Hemorrhagic Fever, Ebola / drug therapy*
  • Hemorrhagic Fever, Ebola / virology
  • Hep G2 Cells
  • Humans
  • Hydrogen-Ion Concentration / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Estrogen / metabolism
  • Selective Estrogen Receptor Modulators / pharmacology
  • Selective Estrogen Receptor Modulators / therapeutic use*
  • Survival Analysis
  • Toremifene / pharmacology
  • Toremifene / therapeutic use
  • United States
  • United States Food and Drug Administration*
  • Vero Cells
  • Virion / drug effects
  • Virus Internalization / drug effects

Substances

  • Receptors, Estrogen
  • Selective Estrogen Receptor Modulators
  • Clomiphene
  • Toremifene
  • Cathepsins