The clinically approved drugs amiodarone, dronedarone and verapamil inhibit filovirus cell entry.
OBJECTIVE
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 anti-arrhythmic 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.
Institute for Molecular Biology, Hannover Medical School, Hannover, Germany Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Gerrit
G
Gehring
Institute for Molecular Biology, Hannover Medical School, Hannover, Germany.
Katrin
K
Rohrmann
Institute for Molecular Biology, Hannover Medical School, Hannover, Germany Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Nkacheh
N
Atenchong
Institute for Virology, University of Marburg, Marburg, Germany.
Eva
E
Mittler
Institute for Virology, University of Marburg, Marburg, Germany.
Stephan
S
Becker
Infection Biology Unit, German Primate Center, Göttingen, Germany.
Franziska
F
Dahlmann
Infection Biology Unit, German Primate Center, Göttingen, Germany.
Stefan
S
Pöhlmann
Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany.
Florian W R
FW
Vondran
Department of Nephrology, Hannover Medical School, Hannover, Germany.
Sascha
S
David
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Michael P
MP
Manns
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Sandra
S
Ciesek
Institute for Molecular Biology, Hannover Medical School, Hannover, Germany Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany vonhahn.thomas@mh-hannover.de.
Thomas
T
von Hahn
D018674:Adrenergic Antagonists / Q000494:pharmacology; D000638:Amiodarone / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D006477:Arenaviruses, New World / Q000187:drug effects; D002043:Bunyaviridae / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002460:Cell Line; D000077764:Dronedarone; D029043:Ebolavirus / Q000187:drug effects*; D006801:Humans; D007836:Lassa virus / Q000187:drug effects; D029024:Marburgvirus / Q000187:drug effects*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects; D053586:Virus Internalization / Q000187:drug effects*
D018674:Adrenergic Antagonists; D002121:Calcium Channel Blockers; D026902:Potassium Channel Blockers; D026941:Sodium Channel Blockers; D014700:Verapamil; D000077764:Dronedarone; D000638:Amiodarone
calcium channels; cationic amphiphiles; haemorrhagic fever