Cross-linking peptide and repurposed drugs inhibit both entry pathways of SARS-CoV-2

Nat Commun. 2021 Mar 9;12(1):1517. doi: 10.1038/s41467-021-21825-w.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology*
  • COVID-19 / virology
  • COVID-19 Drug Treatment*
  • Chlorocebus aethiops
  • Chloroquine / pharmacology
  • Drug Discovery
  • Drug Repositioning*
  • Female
  • HEK293 Cells
  • Humans
  • Indoles / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Peptides / pharmacology*
  • SARS-CoV-2 / drug effects*
  • Serine Endopeptidases / metabolism
  • Vero Cells
  • Virus Internalization / drug effects*


  • Antiviral Agents
  • Indoles
  • Peptides
  • Chloroquine
  • Serine Endopeptidases