TY - JOUR
T1 - Efficacy of tilorone dihydrochloride against ebola virus infection
AU - Ekins, Sean
AU - Lingerfelt, Mary A.
AU - Comer, Jason E.
AU - Freiberg, Alexander N.
AU - Mirsalis, Jon C.
AU - O’Loughlin, Kathleen
AU - Harutyunyan, Anush
AU - McFarlane, Claire
AU - Green, Carol E.
AU - Madrid, Peter B.
N1 - Funding Information:
This project was funded in whole or in part with federal funds from the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract no. HHSN2722011000221 (SRI principal investigator [PI], J.C.M.) and HHSN272201000040I, task order HHSN27200011 (UTMB PI, David Beasley). We also kindly acknowledge NIH funding R21TR001718 from NCATS (PI, S.E.).
Funding Information:
This project was funded in whole or in part with federal funds from the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract no. HHSN2722011000221 (SRI principal investigator [PI], J.C.M.) and HHSN272201000040I, task order HHSN27200011 (UTMB PI, David Beasley). We also kindly acknowledge NIH funding R21TR001718 from NCATS (PI, S.E.). We thank the technical staff at UTMB for performing the high-containment studies, including Terry Juelich, Birte Kalveram, Shane Massey, David Perez, Jennifer Smith, Rose Wanjala, and Lihong Zhang.
Publisher Copyright:
© 2018 American Society for Microbiology. All Rights Reserved.
PY - 2018/2
Y1 - 2018/2
N2 - 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.
AB - 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.
KW - Antiviral
KW - Ebola virus
KW - Ebola virus disease
KW - Interferon inducer
KW - Tilorone
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UR - http://www.scopus.com/inward/citedby.url?scp=85040963085&partnerID=8YFLogxK
U2 - 10.1128/AAC.01711-17
DO - 10.1128/AAC.01711-17
M3 - Article
C2 - 29133569
AN - SCOPUS:85040963085
VL - 62
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 2
M1 - e01711-17
ER -