Abstract
Up to date, effective antivirals have not been widely available for treating COVID-19. In this study, we identify a dual-functional cross-linking peptide 8P9R which can inhibit the two entry pathways (endocytic pathway and TMPRSS2-mediated surface pathway) of SARS-CoV-2 in cells. The endosomal acidification inhibitors (8P9R and chloroquine) can synergistically enhance the activity of arbidol, a spike-ACE2 fusion inhibitor, against SARS-CoV-2 and SARS-CoV in cells. In vivo studies indicate that 8P9R or the combination of repurposed drugs (umifenovir also known as arbidol, chloroquine and camostat which is a TMPRSS2 inhibitor), simultaneously interfering with the two entry pathways of coronaviruses, can significantly suppress SARS-CoV-2 replication in hamsters and SARS-CoV in mice. Here, we use drug combination (arbidol, chloroquine, and camostat) and a dual-functional 8P9R to demonstrate that blocking the two entry pathways of coronavirus can be a promising and achievable approach for inhibiting SARS-CoV-2 replication in vivo. Cocktail therapy of these drug combinations should be considered in treatment trials for COVID-19.
Highlights
Up to date, effective antivirals have not been widely available for treating COVID-19
We developed a dual-functional antiviral peptide 8P9R which could cross-link viruses to block viral entry on cell surface through the TMPRSS2-mediated pathway and simultaneously inhibited endosomal acidification to block viral entry through endocytic pathway
We demonstrated the synergistic antiviral mechanism of endosomal acidification inhibitors (8P9R and chloroquine) on enhancing the activity of arbidol against SARS-CoV-2 and SARS-CoV infection through the endocytic pathway
Summary
Effective antivirals have not been widely available for treating COVID-19. In vivo studies indicate that 8P9R or the combination of repurposed drugs (umifenovir known as arbidol, chloroquine and camostat which is a TMPRSS2 inhibitor), simultaneously interfering with the two entry pathways of coronaviruses, can significantly suppress SARS-CoV-2 replication in hamsters and SARS-CoV in mice. We use drug combination (arbidol, chloroquine, and camostat) and a dual-functional 8P9R to demonstrate that blocking the two entry pathways of coronavirus can be a promising and achievable approach for inhibiting SARS-CoV-2 replication in vivo. Cocktail therapy of these drug combinations should be considered in treatment trials for COVID-19. A cross-linking peptide 8P9R, which is developed from our previously reported P933 and P9R10, has been shown to have dual-antiviral mechanisms of cross-linking viruses to stop viral entry (mediated by TMPRSS2 for SARS-CoV-2) and of reducing endosomal acidification to inhibit viral entry through endocytic pathway. 8P9R shows significantly antiviral activity against SARS-CoV-2 in hamsters and SARS-CoV in mice
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