Pharmacologically induced endolysosomal cholesterol imbalance through clinically licensed drugs itraconazole and fluoxetine impairs Ebola virus infection in vitro

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01105-15 ◽

2015 ◽

Vol 59 (10) ◽

pp. 5892-5902 ◽

Cited By ~ 26

Author(s):

Azizul Haque ◽

Didier Hober ◽

Joel Blondiaux

Keyword(s):

Virus Infection ◽

Ebola Virus ◽

Therapeutic Agent ◽

Cell Types ◽

Rapid Evaluation ◽

Hemorrhagic Disease ◽

Treatment And Prevention ◽

Approved Drugs ◽

Ebola Virus Infection

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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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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