The clinically approved drugs amiodarone, dronedarone and verapamil inhibit filovirus cell entry

Gerrit Gehring, Katrin Rohrmann, Nkacheh Atenchong, Eva-Maria Mittler, Stephan Becker, Franziska Dahlmann, Stefan Pöhlmann, Florian W.R. Vondran, Sascha David, Michael P. Manns, Sandra Ciesek, Thomas von Hahn

Research output: Contribution to journalArticle

97 Citations (Scopus)

Abstract

Objectives: Filoviruses such as Ebola virus and Marburg virus cause a severe haemorrhagic fever syndrome in humans for which there is no specific treatment. Since filoviruses use a complex route of cell entry that depends on numerous cellular factors,we hypothesized that there may be drugs already approved for human use for other indications that interfere with signal transduction or other cellular processes required for their entry and hence have anti-filoviral properties. Methods: We used authentic filoviruses and lentiviral particles pseudotyped with filoviral glycoproteins to identify and characterize such compounds. Results: We discovered that amiodarone, a multi-ion channel inhibitor and adrenoceptor antagonist, is a potent inhibitor of filovirus cell entry at concentrations that are routinely reached in human serum during antiarrhythmic therapy. A similar effect was observed with the amiodarone-related agent dronedarone and the L-type calcium channel blocker verapamil. Inhibition by amiodarone was concentration dependent and similarly affected pseudoviruses as well as authentic filoviruses. Inhibition of filovirus entry was observed with most but not all cell types tested and was accentuated by the pre-treatment of cells, indicating a host cell-directed mechanism of action. The New World arenavirus Guanarito was also inhibited by amiodarone while the Old World arenavirus Lassa and members of the Rhabdoviridae (vesicular stomatitis virus) and Bunyaviridae (Hantaan) families were largely resistant. Conclusions: The ion channel blockers amiodarone, dronedarone and verapamil inhibit filoviral cell entry.

Original languageEnglish (US)
Article numberdku091
Pages (from-to)2123-2131
Number of pages9
JournalJournal of Antimicrobial Chemotherapy
Volume69
Issue number8
DOIs
StatePublished - Jan 1 2014

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Amiodarone
Verapamil
Pharmaceutical Preparations
Ion Channels
Old World Arenaviruses
New World Arenaviruses
Marburgvirus
Hantaan virus
Bunyaviridae
Rhabdoviridae
Ebolavirus
L-Type Calcium Channels
Vesicular Stomatitis
Calcium Channel Blockers
Adrenergic Receptors
dronedarone
Signal Transduction
Glycoproteins
Fever
Therapeutics

Keywords

  • Calcium channels
  • Cationic amphiphiles
  • Haemorrhagic fever

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Gehring, G., Rohrmann, K., Atenchong, N., Mittler, E-M., Becker, S., Dahlmann, F., ... von Hahn, T. (2014). The clinically approved drugs amiodarone, dronedarone and verapamil inhibit filovirus cell entry. Journal of Antimicrobial Chemotherapy, 69(8), 2123-2131. [dku091]. https://doi.org/10.1093/jac/dku091

The clinically approved drugs amiodarone, dronedarone and verapamil inhibit filovirus cell entry. / Gehring, Gerrit; Rohrmann, Katrin; Atenchong, Nkacheh; Mittler, Eva-Maria; Becker, Stephan; Dahlmann, Franziska; Pöhlmann, Stefan; Vondran, Florian W.R.; David, Sascha; Manns, Michael P.; Ciesek, Sandra; von Hahn, Thomas.

In: Journal of Antimicrobial Chemotherapy, Vol. 69, No. 8, dku091, 01.01.2014, p. 2123-2131.

Research output: Contribution to journalArticle

Gehring, G, Rohrmann, K, Atenchong, N, Mittler, E-M, Becker, S, Dahlmann, F, Pöhlmann, S, Vondran, FWR, David, S, Manns, MP, Ciesek, S & von Hahn, T 2014, 'The clinically approved drugs amiodarone, dronedarone and verapamil inhibit filovirus cell entry', Journal of Antimicrobial Chemotherapy, vol. 69, no. 8, dku091, pp. 2123-2131. https://doi.org/10.1093/jac/dku091
Gehring, Gerrit ; Rohrmann, Katrin ; Atenchong, Nkacheh ; Mittler, Eva-Maria ; Becker, Stephan ; Dahlmann, Franziska ; Pöhlmann, Stefan ; Vondran, Florian W.R. ; David, Sascha ; Manns, Michael P. ; Ciesek, Sandra ; von Hahn, Thomas. / The clinically approved drugs amiodarone, dronedarone and verapamil inhibit filovirus cell entry. In: Journal of Antimicrobial Chemotherapy. 2014 ; Vol. 69, No. 8. pp. 2123-2131.
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abstract = "Objectives: Filoviruses such as Ebola virus and Marburg virus cause a severe haemorrhagic fever syndrome in humans for which there is no specific treatment. Since filoviruses use a complex route of cell entry that depends on numerous cellular factors,we hypothesized that there may be drugs already approved for human use for other indications that interfere with signal transduction or other cellular processes required for their entry and hence have anti-filoviral properties. Methods: We used authentic filoviruses and lentiviral particles pseudotyped with filoviral glycoproteins to identify and characterize such compounds. Results: We discovered that amiodarone, a multi-ion channel inhibitor and adrenoceptor antagonist, is a potent inhibitor of filovirus cell entry at concentrations that are routinely reached in human serum during antiarrhythmic therapy. A similar effect was observed with the amiodarone-related agent dronedarone and the L-type calcium channel blocker verapamil. Inhibition by amiodarone was concentration dependent and similarly affected pseudoviruses as well as authentic filoviruses. Inhibition of filovirus entry was observed with most but not all cell types tested and was accentuated by the pre-treatment of cells, indicating a host cell-directed mechanism of action. The New World arenavirus Guanarito was also inhibited by amiodarone while the Old World arenavirus Lassa and members of the Rhabdoviridae (vesicular stomatitis virus) and Bunyaviridae (Hantaan) families were largely resistant. Conclusions: The ion channel blockers amiodarone, dronedarone and verapamil inhibit filoviral cell entry.",
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AU - Mittler, Eva-Maria

AU - Becker, Stephan

AU - Dahlmann, Franziska

AU - Pöhlmann, Stefan

AU - Vondran, Florian W.R.

AU - David, Sascha

AU - Manns, Michael P.

AU - Ciesek, Sandra

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N2 - Objectives: Filoviruses such as Ebola virus and Marburg virus cause a severe haemorrhagic fever syndrome in humans for which there is no specific treatment. Since filoviruses use a complex route of cell entry that depends on numerous cellular factors,we hypothesized that there may be drugs already approved for human use for other indications that interfere with signal transduction or other cellular processes required for their entry and hence have anti-filoviral properties. Methods: We used authentic filoviruses and lentiviral particles pseudotyped with filoviral glycoproteins to identify and characterize such compounds. Results: We discovered that amiodarone, a multi-ion channel inhibitor and adrenoceptor antagonist, is a potent inhibitor of filovirus cell entry at concentrations that are routinely reached in human serum during antiarrhythmic therapy. A similar effect was observed with the amiodarone-related agent dronedarone and the L-type calcium channel blocker verapamil. Inhibition by amiodarone was concentration dependent and similarly affected pseudoviruses as well as authentic filoviruses. Inhibition of filovirus entry was observed with most but not all cell types tested and was accentuated by the pre-treatment of cells, indicating a host cell-directed mechanism of action. The New World arenavirus Guanarito was also inhibited by amiodarone while the Old World arenavirus Lassa and members of the Rhabdoviridae (vesicular stomatitis virus) and Bunyaviridae (Hantaan) families were largely resistant. Conclusions: The ion channel blockers amiodarone, dronedarone and verapamil inhibit filoviral cell entry.

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