Abstract
The 2019 novel respiratory virus (SARS-CoV-2) causes COVID-19 with rapid global socioeconomic disruptions and disease burden to healthcare. The COVID-19 and previous emerging virus outbreaks highlight the urgent need for broad-spectrum antivirals. Here, we show that a defensin-like peptide P9R exhibited potent antiviral activity against pH-dependent viruses that require endosomal acidification for virus infection, including the enveloped pandemic A(H1N1)pdm09 virus, avian influenza A(H7N9) virus, coronaviruses (SARS-CoV-2, MERS-CoV and SARS-CoV), and the non-enveloped rhinovirus. P9R can significantly protect mice from lethal challenge by A(H1N1)pdm09 virus and shows low possibility to cause drug-resistant virus. Mechanistic studies indicate that the antiviral activity of P9R depends on the direct binding to viruses and the inhibition of virus-host endosomal acidification, which provides a proof of concept that virus-binding alkaline peptides can broadly inhibit pH-dependent viruses. These results suggest that the dual-functional virus- and host-targeting P9R can be a promising candidate for combating pH-dependent respiratory viruses.
Highlights
The 2019 novel respiratory virus (SARS-CoV-2) causes COVID-19 with rapid global socioeconomic disruptions and disease burden to healthcare
We have previously reported a broad-spectrum antiviral peptide P913, derived from mouse β-defensin-4, which showed antiviral activity against SARS-CoV, MERS-CoV, and influenza viruses through the inhibition of endosomal acidification
To further confirm that the broad-spectrum antiviral activity of P9R was due to the broad spectrum of binding of P9R to different viruses and viral proteins, we demonstrated that P9R but not P9RS could bind to MERS-CoV, A(H7N9) virus, rhinovirus, SARS-CoV and viral proteins (Fig. 3d–f and Supplementary Fig. 8)
Summary
The 2019 novel respiratory virus (SARS-CoV-2) causes COVID-19 with rapid global socioeconomic disruptions and disease burden to healthcare. Mechanistic studies indicate that the antiviral activity of P9R depends on the direct binding to viruses and the inhibition of virus-host endosomal acidification, which provides a proof of concept that virus-binding alkaline peptides can broadly inhibit pH-dependent viruses. These results suggest that the dual-functional virusand host-targeting P9R can be a promising candidate for combating pH-dependent respiratory viruses. Due to the lack of effective antivirals, especially for coronaviruses, these respiratory viruses are associated with significantly high morbidity and mortality These emerging respiratory viruses have caused severe economic and social disturbances. We have previously reported a broad-spectrum antiviral peptide P913, derived from mouse β-defensin-4, which showed antiviral activity against SARS-CoV, MERS-CoV, and influenza viruses through the inhibition of endosomal acidification. Since the first anti-HIV peptide enfuvirtide was approved by FDA for the treatment of HIV in 200325, other peptides with antiviral activity have been approved by FDA26
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