Repurposing the antimalarial pyronaridine tetraphosphate to protect against Ebola virus infection

Author summary To date there is no approved drug for Ebola Virus infection. Our approach has been to assess drugs that are already approved for other uses in various countries. Using computational models, we have previously identified three such drugs and demonstrated their activity against the Ebola virus in vitro. We now report on the in vitro absorption, metabolism, distribution, excretion and pharmacokinetic properties of one of these molecules, namely the antimalarial pyronaridine. We justify efficacy testing in the mouse model of ebola infection. We also demonstrate that a single dose of this drug is 100% effective against the virus. This study provides important preclinical evaluation of this already approved drug and justifies its selection for larger animal efficacy studies. Recent outbreaks of the Ebola virus (EBOV) have focused attention on the dire need for antivirals to treat these patients. We identified pyronaridine tetraphosphate as a potential candidate as it is an approved drug in the European Union which is currently used in combination with artesunate as a treatment for malaria (EC50 between 420 nM-1.14 mu M against EBOV in HeLa cells). Range-finding studies in mice directed us to a single 75 mg/kg i.p. dose 1 hr after infection which resulted in 100% survival and statistically significantly reduced viremia at 21 days from a lethal challenge with mouse-adapted EBOV (maEBOV). Further, an EBOV window study suggested we could dose pyronaridine 2 or 24 hrs post-exposure to result in similar efficacy. Analysis of cytokine and chemokine panels suggests that pyronaridine may act as an immunomodulator during an EBOV infection. Our studies with pyronaridine clearly demonstrate potential utility for its repurposing as an antiviral against EBOV and merits further study in larger animal models with the added benefit of already being used as a treatment against malaria.