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Antimicrob Agents Chemother. 2018 Jan 25;62(2). pii: e01711-17. doi: 10.1128/AAC.01711-17. Print 2018 Feb.

Efficacy of Tilorone Dihydrochloride against Ebola Virus Infection.

Author information

1
Collaborations Pharmaceuticals, Inc., Raleigh, North Carolina, USA.
2
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
3
Institutional Office of Regulated Nonclinical Studies, University of Texas Medical Branch, Galveston, Texas, USA.
4
Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, USA.
5
Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
6
Bioscience Division, SRI International, Menlo Park, California, USA.
7
Bioscience Division, SRI International, Menlo Park, California, USA peter.madrid@sri.com.

Abstract

Tilorone dihydrochloride (tilorone) is a small-molecule, orally bioavailable drug that is used clinically as an antiviral outside the United States. A machine-learning model trained on anti-Ebola virus (EBOV) screening data previously identified tilorone as a potent in vitro EBOV inhibitor, making it a candidate for the treatment of Ebola virus disease (EVD). In the present study, a series of in vitro ADMET (absorption, distribution, metabolism, excretion, toxicity) assays demonstrated the drug has excellent solubility, high Caco-2 permeability, was not a P-glycoprotein substrate, and had no inhibitory activity against five human CYP450 enzymes (3A4, 2D6, 2C19, 2C9, and 1A2). Tilorone was shown to have 52% human plasma protein binding with excellent plasma stability and a mouse liver microsome half-life of 48 min. Dose range-finding studies in mice demonstrated a maximum tolerated single dose of 100 mg/kg of body weight. A pharmacokinetics study in mice at 2- and 10-mg/kg dose levels showed that the drug is rapidly absorbed, has dose-dependent increases in maximum concentration of unbound drug in plasma and areas under the concentration-time curve, and has a half-life of approximately 18 h in both males and females, although the exposure was ∼2.5-fold higher in male mice. Tilorone doses of 25 and 50 mg/kg proved efficacious in protecting 90% of mice from a lethal challenge with mouse-adapted with once-daily intraperitoneal (i.p.) dosing for 8 days. A subsequent study showed that 30 mg/kg/day of tilorone given i.p. starting 2 or 24 h postchallenge and continuing through day 7 postinfection was fully protective, indicating promising activity for the treatment of EVD.

KEYWORDS:

Ebola virus; Ebola virus disease; antiviral; interferon inducer; tilorone

PMID:
29133569
PMCID:
PMC5786809
DOI:
10.1128/AAC.01711-17
[Indexed for MEDLINE]
Free PMC Article

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