Pyronaridine Tetraphosphate Efficacy Against Ebola Virus Infection in Guinea Pig

Lane, T. R.; Massey, C.; Comer, J. E.; Freiberg, A. N.; Zhou, H.; Dyall, J.; Holbrook, M.; Anantpadma, M.; Davey, R. A.; Madrid, P.; Ekins, S.

doi:10.1101/2020.03.20.001081

bioRxiv · 10.1101/2020.03.20.001081

Pyronaridine Tetraphosphate Efficacy Against Ebola Virus Infection in Guinea Pig

Lane, T. R.·Massey, C.·Comer, J. E.·Freiberg, A. N.·Zhou, H.·Dyall, J.·Holbrook, M.·Anantpadma, M.·Davey, R. A.·Madrid, P.·Ekins, S.

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Abstract

The 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 {micro}M against three strains of EBOV and IC50 range of 1.01-2.72 {micro}M 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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Lane, T. R., Massey, C., Comer, J. E., Freiberg, A. N., Zhou, H., Dyall, J., Holbrook, M., Anantpadma, M., Davey, R. A., Madrid, P., Ekins, S.. 2020-03-23. Pyronaridine Tetraphosphate Efficacy Against Ebola Virus Infection in Guinea Pig. https://doi.org/10.1101/2020.03.20.001081

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