TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation

Cell. 2021 May 13;184(10):2618-2632.e17. doi: 10.1016/j.cell.2021.03.051. Epub 2021 Mar 30.


The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro, and in vivo analyses, we report that topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of topotecan (TPT), an FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as 4 days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe coronavirus disease 2019 (COVID-19) in humans.

Keywords: COVID-19; SARS-CoV-2; chromatin; cytokine storm; epigenetics; inducible genes; inflammation; topoisomerase; topotecan; transcription.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COVID-19 / enzymology
  • COVID-19 / pathology
  • COVID-19 Drug Treatment*
  • Chlorocebus aethiops
  • DNA Topoisomerases, Type I / metabolism*
  • Humans
  • Inflammation / drug therapy
  • Inflammation / enzymology
  • Inflammation / pathology
  • Inflammation / virology
  • Mesocricetus
  • Mice
  • Mice, Transgenic
  • SARS-CoV-2 / metabolism*
  • THP-1 Cells
  • Topoisomerase I Inhibitors / pharmacology*
  • Topotecan / pharmacology*
  • Vero Cells


  • Topoisomerase I Inhibitors
  • Topotecan
  • DNA Topoisomerases, Type I
  • TOP1 protein, human