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Repurposing the antimalarial pyronaridine tetraphosphate to protect against Ebola virus infection.

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 ?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 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.

SUBMITTER: Lane TR

PROVIDER: S-EPMC6894882 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Repurposing the antimalarial pyronaridine tetraphosphate to protect against Ebola virus infection.

Lane Thomas R TR Massey Christopher C Comer Jason E JE Anantpadma Manu M Freundlich Joel S JS Davey Robert A RA Madrid Peter B PB Ekins Sean S

PLoS neglected tropical diseases 20191121 11

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% survi ...[more]

PMID: 31751347

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Project description:The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), continues to be one of the largest dangers to human health around the world. The need for effective antiviral and anti-inflammatory treatments is still extremely high as newly emerging variants threaten the efficacy of currently used treatment options. Many compounds are effective at inhibiting SARS-CoV-2 infection in vitro but fail to recapitulate that efficacy in vivo. There is a major demand for antiviral drugs that are efficacious and broadly effective for the treatment of highly pathogenic coronaviruses including SARS-CoV-2, and its close relatives SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). One drug with the potential to join the small subset of broadly active antiviral compounds that is both efficacious in vivo and orally bioavailable is pyronaridine triphosphate, which has now been published to show both in vitro and in vivo efficacy in A549 cells and the K18-hACE2 mouse model, respectively, by functioning as a protease inhibitor of the SARS-CoV-2 papain-like protease (PLpro). In our studies, pyronaridine treatment resulted in significant improvements to lung inflammatory pathology, reducing pro-inflammatory cytokine and chemokine levels, and inhibiting weight loss seen in the mouse model associated with the severity of disease in three highly pathogenic coronavirus infection models, SARS-CoV-1, SARS-CoV-2, and MERS-CoV. Additionally, we found that pyronaridine treatment can safely and effectively be combined with currently used therapeutics molnupiravir and nirmatrelvir (main protease inhibitor component of Paxlovid) in a SARS-CoV-2 in vivo model, and there was evidence of a synergistic effect that further reduced viral titers, inflammatory lung pathology, and inflammatory cytokine and chemokine levels. These results indicate that pyronaridine represents an excellent potential therapeutic candidate for COVID-19 treatment individually, or in combination with other approved antivirals as well as a potential therapeutic option for the treatment of highly pathogenic coronaviruses such as SARS-CoV-1, MERS-CoV, and future coronaviruses yet to emerge. IMPORTANCE Pyronaridine tetraphosphate is on the WHO Essential Medicine List for its importance as a widely available and safe treatment for malaria. We find that pyronaridine is a highly effective antiviral therapeutic across mouse models using multiple variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and the highly pathogenic viruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus responsible for previous coronavirus outbreaks. Additionally, we find that pyronaridine additively combines with current COVID-19 treatments such as nirmatrelvir (protease inhibitor in Paxlovid) and molnupiravir to further inhibit SARS-CoV-2 infections. There are many antiviral compounds that demonstrate efficacy in cellular models, but few that show this level of impact in multiple mouse models and represent a promising therapeutic for the current coronavirus pandemic as well as future outbreaks as well.

Dataset Information

Repurposing the antimalarial pyronaridine tetraphosphate to protect against Ebola virus infection.

Publications

Repurposing the antimalarial pyronaridine tetraphosphate to protect against Ebola virus infection.

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