Pyronaridine tetraphosphate is an efficacious antiviral and anti-inflammatory active against multiple highly pathogenic coronaviruses

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 em...

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Autores principales: Ardanuy, Jeremy, Johnson, Robert, Dillen, Carly, Taylor, Louis, Hammond, Holly, Weston, Stuart, Frieman, Matthew
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10653794/
https://www.ncbi.nlm.nih.gov/pubmed/37581442
http://dx.doi.org/10.1128/mbio.01587-23
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author Ardanuy, Jeremy
Johnson, Robert
Dillen, Carly
Taylor, Louis
Hammond, Holly
Weston, Stuart
Frieman, Matthew
author_facet Ardanuy, Jeremy
Johnson, Robert
Dillen, Carly
Taylor, Louis
Hammond, Holly
Weston, Stuart
Frieman, Matthew
author_sort Ardanuy, Jeremy
collection PubMed
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.
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spelling pubmed-106537942023-08-15 Pyronaridine tetraphosphate is an efficacious antiviral and anti-inflammatory active against multiple highly pathogenic coronaviruses Ardanuy, Jeremy Johnson, Robert Dillen, Carly Taylor, Louis Hammond, Holly Weston, Stuart Frieman, Matthew mBio Research Article 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. American Society for Microbiology 2023-08-15 /pmc/articles/PMC10653794/ /pubmed/37581442 http://dx.doi.org/10.1128/mbio.01587-23 Text en Copyright © 2023 Ardanuy et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Ardanuy, Jeremy
Johnson, Robert
Dillen, Carly
Taylor, Louis
Hammond, Holly
Weston, Stuart
Frieman, Matthew
Pyronaridine tetraphosphate is an efficacious antiviral and anti-inflammatory active against multiple highly pathogenic coronaviruses
title Pyronaridine tetraphosphate is an efficacious antiviral and anti-inflammatory active against multiple highly pathogenic coronaviruses
title_full Pyronaridine tetraphosphate is an efficacious antiviral and anti-inflammatory active against multiple highly pathogenic coronaviruses
title_fullStr Pyronaridine tetraphosphate is an efficacious antiviral and anti-inflammatory active against multiple highly pathogenic coronaviruses
title_full_unstemmed Pyronaridine tetraphosphate is an efficacious antiviral and anti-inflammatory active against multiple highly pathogenic coronaviruses
title_short Pyronaridine tetraphosphate is an efficacious antiviral and anti-inflammatory active against multiple highly pathogenic coronaviruses
title_sort pyronaridine tetraphosphate is an efficacious antiviral and anti-inflammatory active against multiple highly pathogenic coronaviruses
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10653794/
https://www.ncbi.nlm.nih.gov/pubmed/37581442
http://dx.doi.org/10.1128/mbio.01587-23
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