Evaluation of Ebola Virus Inhibitors for Drug Repurposing.
A systematic screen of FDA-approved drugs was performed to identify compounds with in vitro antiviral activities against Ebola virus (EBOV). Compounds active (>50% viral inhibition and <30% cellular toxicity) at a single concentration were tested in dose-response assays to quantitate the antiviral activities in replication and viral entry assays as well as cytotoxicity in the Vero cell line used to conduct these assays. On the basis of the approved human dosing, toxicity/tolerability, and pharmacokinetic data, seven of these in vitro hits from different pharmacological classes (chloroquine (CQ), amiodarone, prochlorperazine, benztropine, azithromycin, chlortetracycline, and clomiphene) were evaluated for their in vivo efficacy at a single dose and were administered via either intraperitoneal (ip) or oral route. Initially, azithromycin (100 mg/kg, twice daily, ip), CQ (90 mg/kg, twice daily, ip), and amiodarone (60 mg/kg, twice daily, ip) demonstrated significant increases in survival in the mouse model. After repeat evaluation, only CQ was found to reproducibly give significant efficacy in the mouse model with this dosing regimen. Azithromycin and CQ were also tested in a guinea pig model of EBOV infection over a range of doses, but none of the doses increased survival, and drug-related toxicity was observed at lower doses than in the mouse. These results show the benefits and specific challenges associated with drug repurposing and highlight the need for careful evaluation of approved drugs as rapidly deployable countermeasures against future pandemics.
Biosciences Division, SRI International , 333 Ravenswood Avenue, Menlo Park, California 94025, United States.
Peter B
PB
Madrid
U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick , 1425 Porter Street, Frederick, Maryland 21702, United States.
Rekha G
RG
Panchal
U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick , 1425 Porter Street, Frederick, Maryland 21702, United States.
Travis K
TK
Warren
U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick , 1425 Porter Street, Frederick, Maryland 21702, United States.
Amy C
AC
Shurtleff
Biosciences Division, SRI International , 333 Ravenswood Avenue, Menlo Park, California 94025, United States.
Aaron N
AN
Endsley
Biosciences Division, SRI International , 333 Ravenswood Avenue, Menlo Park, California 94025, United States.
Carol E
CE
Green
University of Texas Medical Branch at Galveston , 301 University Boulevard, Galveston, Texas 77555, United States.
Andrey
A
Kolokoltsov
University of Texas Medical Branch at Galveston , 301 University Boulevard, Galveston, Texas 77555, United States.
Robert
R
Davey
Biosciences Division, SRI International , 333 Ravenswood Avenue, Menlo Park, California 94025, United States.
Ian D
ID
Manger
Biosciences Division, SRI International , 333 Ravenswood Avenue, Menlo Park, California 94025, United States.
Lynne
L
Gilfillan
U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick , 1425 Porter Street, Frederick, Maryland 21702, United States.
Sina
S
Bavari
Biosciences Division, SRI International , 333 Ravenswood Avenue, Menlo Park, California 94025, United States.
Mary J
MJ
Tanga
Ebola; cellular toxicity; chloroquine; drug repurposing; viral inhibition