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 emerging variants threaten the efficacy of currently used treatment options. Many compounds are effective at inhibiting SARS-CoV-2 infection but fail to recapitulate that efficacy . 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 and orally bioavailable is pyronaridine triphosphate, which has now been published to show both and 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 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.