Efficacy of tilorone dihydrochloride against ebola virus infection

Sean Ekins, Mary A. Lingerfelt, Jason Comer, Alexander Freiberg, Jon C. Mirsalis, Kathleen O’Loughlin, Anush Harutyunyan, Claire McFarlane, Carol E. Green, Peter B. Madrid

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere01711-17
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number2
DOIs
StatePublished - Feb 1 2018

Fingerprint

Ebola Hemorrhagic Fever
Tilorone
Ebolavirus
Pharmaceutical Preparations
Half-Life
Maximum Tolerated Dose
P-Glycoprotein
Liver Microsomes
Protein Binding
Solubility
Antiviral Agents
Blood Proteins
Permeability
Pharmacokinetics
Body Weight
Enzymes

Keywords

  • Antiviral
  • Ebola virus
  • Ebola virus disease
  • Interferon inducer
  • Tilorone

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Ekins, S., Lingerfelt, M. A., Comer, J., Freiberg, A., Mirsalis, J. C., O’Loughlin, K., ... Madrid, P. B. (2018). Efficacy of tilorone dihydrochloride against ebola virus infection. Antimicrobial Agents and Chemotherapy, 62(2), [e01711-17]. https://doi.org/10.1128/AAC.01711-17

Efficacy of tilorone dihydrochloride against ebola virus infection. / Ekins, Sean; Lingerfelt, Mary A.; Comer, Jason; Freiberg, Alexander; Mirsalis, Jon C.; O’Loughlin, Kathleen; Harutyunyan, Anush; McFarlane, Claire; Green, Carol E.; Madrid, Peter B.

In: Antimicrobial Agents and Chemotherapy, Vol. 62, No. 2, e01711-17, 01.02.2018.

Research output: Contribution to journalArticle

Ekins, S, Lingerfelt, MA, Comer, J, Freiberg, A, Mirsalis, JC, O’Loughlin, K, Harutyunyan, A, McFarlane, C, Green, CE & Madrid, PB 2018, 'Efficacy of tilorone dihydrochloride against ebola virus infection', Antimicrobial Agents and Chemotherapy, vol. 62, no. 2, e01711-17. https://doi.org/10.1128/AAC.01711-17
Ekins S, Lingerfelt MA, Comer J, Freiberg A, Mirsalis JC, O’Loughlin K et al. Efficacy of tilorone dihydrochloride against ebola virus infection. Antimicrobial Agents and Chemotherapy. 2018 Feb 1;62(2). e01711-17. https://doi.org/10.1128/AAC.01711-17
Ekins, Sean ; Lingerfelt, Mary A. ; Comer, Jason ; Freiberg, Alexander ; Mirsalis, Jon C. ; O’Loughlin, Kathleen ; Harutyunyan, Anush ; McFarlane, Claire ; Green, Carol E. ; Madrid, Peter B. / Efficacy of tilorone dihydrochloride against ebola virus infection. In: Antimicrobial Agents and Chemotherapy. 2018 ; Vol. 62, No. 2.
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