Abstract
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 μM 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 study day 3 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.
Highlights
Ebola virus (EBOV) is a member of the family filovirus
We have previously identified three such drugs and demonstrated their activity against the Ebola virus in vitro
We demonstrate that a single dose of this drug is 100% effective against the virus
Summary
Ebola virus (EBOV) is a member of the family filovirus. Filoviruses are pathogenic against both humans and non-human primates and cause severe hemorrhagic fevers [1] with mortality rates as high as 90% [2, 3]. Compounds which are FDA-approved (or European EMA approved) drugs for other diseases [15, 24, 25], but have activity against EBOV in vitro or in vivo may represent useful starting points with the advantage that much is known regarding their absorption, distribution, metabolism and excretion (ADME) and toxicity properties. These repurposed drugs represent an advanced starting point for therapeutic development and approval compared with new chemical entities [26]. While there is considerable data on pyronaridine as a chemotherapeutic for malaria [31], this study describes the first reported efficacy of pyronaridine to treat maEBOV-infected mice
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