Addressing Therapeutic Options for Ebola Virus Infection in Current and Future Outbreaks

ABSTRACTEbola virus can cause severe hemorrhagic disease with high fatality rates. Currently, no specific therapeutic agent or vaccine has been approved for treatment and prevention of Ebola virus infection of humans. Although the number of Ebola cases has fallen in the last few weeks, multiple outbreaks of Ebola virus infection and the likelihood of future exposure highlight the need for development and rapid evaluation of pre- and postexposure treatments. Here, we briefly review the existing and future options for anti-Ebola therapy, based on the data coming from rare clinical reports, studies on animals, and results fromin vitromodels. We also project the mechanistic hypotheses of several potential drugs against Ebola virus, including small-molecule-based drugs, which are under development and being tested in animal models orin vitrousing various cell types. Our paper discusses strategies toward identifying and testing anti-Ebola virus properties of known and medically approved drugs, especially those that can limit the pathological inflammatory response in Ebola patients and thereby provide protection from mortality. We underline the importance of developing combinational therapy for better treatment outcomes for Ebola patients.

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Antibody-Dependent Enhancement of Ebola Virus Infection

Journal of Virology ◽

10.1128/jvi.77.13.7539-7544.2003 ◽

2003 ◽

Vol 77 (13) ◽

pp. 7539-7544 ◽

Cited By ~ 119

Author(s):

Ayato Takada ◽

Heinz Feldmann ◽

Thomas G. Ksiazek ◽

Yoshihiro Kawaoka

Keyword(s):

Virus Infection ◽

Ebola Virus ◽

Human Populations ◽

Hemorrhagic Disease ◽

Viral Infectivity ◽

Kidney Cells ◽

Emerging Pathogens ◽

Viral Glycoprotein ◽

Antibody Dependent Enhancement ◽

Ebola Virus Infection

ABSTRACT Most strains of Ebola virus cause a rapidly fatal hemorrhagic disease in humans, yet there are still no biologic explanations that adequately account for the extreme virulence of these emerging pathogens. Here we show that Ebola Zaire virus infection in humans induces antibodies that enhance viral infectivity. Plasma or serum from convalescing patients enhanced the infection of primate kidney cells by the Zaire virus, and this enhancement was mediated by antibodies to the viral glycoprotein and by complement component C1q. Our results suggest a novel mechanism of antibody-dependent enhancement of Ebola virus infection, one that would account for the dire outcome of Ebola outbreaks in human populations.

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Possible FDA-approved drugs to treat Ebola virus infection

Infectious Diseases of Poverty ◽

10.1186/s40249-015-0055-z ◽

2015 ◽

Vol 4 (1) ◽

Cited By ~ 13

Author(s):

Shu Yuan

Keyword(s):

Virus Infection ◽

Ebola Virus ◽

Approved Drugs ◽

Fda Approved Drugs ◽

Ebola Virus Infection

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Repurposing Quinacrine against Ebola Virus Infection In Vivo

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01142-19 ◽

2019 ◽

Vol 63 (9) ◽

Cited By ~ 7

Author(s):

Thomas R. Lane ◽

Jason E. Comer ◽

Alexander N. Freiberg ◽

Peter B. Madrid ◽

Sean Ekins

Keyword(s):

Machine Learning ◽

Virus Infection ◽

Ebola Virus ◽

Lethal Challenge ◽

Once Daily ◽

Machine Learning Model ◽

Orally Bioavailable ◽

Ebola Virus Infection

ABSTRACT Quinacrine hydrochloride is a small-molecule, orally bioavailable drug that has been used clinically as an antimalarial and for many other applications. A machine learning model trained on Ebola virus (EBOV) screening data identified quinacrine as a potent (nanomolar) in vitro inhibitor. In the current study, quinacrine 25 mg/kg was shown to protect 70% of mice (statistically significant) from a lethal challenge with mouse-adapted EBOV with once-daily intraperitoneal dosing for 8 days.

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Pyronaridine Tetraphosphate Efficacy Against Ebola Virus Infection in Guinea Pig

10.1101/2020.03.20.001081 ◽

2020 ◽

Cited By ~ 4

Author(s):

Thomas R. Lane ◽

Christopher Massey ◽

Jason E. Comer ◽

Alexander N. Freiberg ◽

Huanying Zhou ◽

...

Keyword(s):

Virus Infection ◽

Guinea Pig ◽

Small Molecule ◽

Ebola Virus ◽

Marburg Virus ◽

Pig Model ◽

Significant Efficacy ◽

Guinea Pig Model ◽

Ebola Virus Infection

AbstractThe recent outbreaks of the Ebola virus (EBOV) in Africa have brought global visibility to the shortage of available therapeutic options to treat patients infected with this or closely related viruses. We have recently computationally identified three molecules which have all demonstrated statistically significant efficacy in the mouse model of infection with mouse adapted Ebola virus (ma-EBOV). One of these molecules is the antimalarial pyronaridine tetraphosphate (IC50 range of 0.82-1.30 µM against three strains of EBOV and IC50 range of 1.01-2.72 µM against two strains of Marburg virus (MARV)) which is an approved drug in the European Union and used in combination with artesunate. To date, no small molecule drugs have shown statistically significant efficacy in the guinea pig model of EBOV infection. Pharmacokinetics and range-finding studies in guinea pigs directed us to a single 300mg/kg or 600mg/kg oral dose of pyronaridine 1hr after infection. Pyronaridine resulted in statistically significant survival of 40% at 300mg/kg and protected from a lethal challenge with EBOV. In comparison, oral favipiravir (300 mg/kg dosed once a day) had 43.5 % survival. The in vitro metabolism and metabolite identification of pyronaridine and another of our EBOV active molecules, tilorone, which suggests significant species differences which may account for the efficacy or lack thereof, respectively in guinea pig. In summary, our studies with pyronaridine demonstrates its utility for repurposing as an antiviral against EBOV and MARV, providing justification for future testing in non-human primates.ImportanceThere is currently no antiviral small molecule drug approved for treating Ebola Virus infection. We have previously used machine learning models to identify new uses for approved drugs and demonstrated their activity against the Ebola virus in vitro and in vivo. We now describe the pharmacokinetic properties of the antimalarial pyronaridine in the guinea pig. In addition, we show that this drug is effective against multiple strains of EBOV and MARV in vitro and in the guinea pig model of Ebola virus infection. These combined efforts indicate the need to further test this molecule in larger animal efficacy studies prior to clinical use in humans. These findings also may be useful for repurposing this drug for use against other viruses in future.

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Virtual screen for repurposing approved and experimental drugs for candidate inhibitors of EBOLA virus infection

F1000Research ◽

10.12688/f1000research.6110.1 ◽

2015 ◽

Vol 4 ◽

pp. 34 ◽

Cited By ~ 28

Author(s):

Veljko Veljkovic ◽

Philippe M. Loiseau ◽

Bruno Figadere ◽

Sanja Glisic ◽

Nevena Veljkovic ◽

...

Keyword(s):

Virtual Screening ◽

Virus Infection ◽

Ebola Virus ◽

Virus Disease ◽

Virtual Screen ◽

Experimental Drugs ◽

Theoretical Criterion ◽

Approved Drugs ◽

Molecular Libraries ◽

Ebola Virus Infection

The ongoing Ebola virus epidemic has presented numerous challenges with respect to control and treatment because there are no approved drugs or vaccines for the Ebola virus disease (EVD). Herein is proposed simple theoretical criterion for fast virtual screening of molecular libraries for candidate inhibitors of Ebola virus infection. We performed a repurposing screen of 6438 drugs from DrugBank using this criterion and selected 267 approved and 382 experimental drugs as candidates for treatment of EVD including 15 anti-malarial drugs and 32 antibiotics. An open source Web server allowing screening of molecular libraries for candidate drugs for treatment of EVD was also established.

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