HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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

Abstract
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.
AuthorsJessica Sook Yuin Ho, Bobo Wing-Yee Mok, Laura Campisi, Tristan Jordan, Soner Yildiz, Sreeja Parameswaran, Joseph A Wayman, Natasha N Gaudreault, David A Meekins, Sabarish V Indran, Igor Morozov, Jessie D Trujillo, Yesai S Fstkchyan, Raveen Rathnasinghe, Zeyu Zhu, Simin Zheng, Nan Zhao, Kris White, Helen Ray-Jones, Valeriya Malysheva, Michiel J Thiecke, Siu-Ying Lau, Honglian Liu, Anna Junxia Zhang, Andrew Chak-Yiu Lee, Wen-Chun Liu, Sonia Jangra, Alba Escalera, Teresa Aydillo, Betsaida Salom Melo, Ernesto Guccione, Robert Sebra, Elaine Shum, Jan Bakker, David A Kaufman, Andre L Moreira, Mariano Carossino, Udeni B R Balasuriya, Minji Byun, Randy A Albrecht, Michael Schotsaert, Adolfo Garcia-Sastre, Sumit K Chanda, Emily R Miraldi, Anand D Jeyasekharan, Benjamin R TenOever, Mikhail Spivakov, Matthew T Weirauch, Sven Heinz, Honglin Chen, Christopher Benner, Juergen A Richt, Ivan Marazzi
JournalCell (Cell) Vol. 184 Issue 10 Pg. 2618-2632.e17 (05 13 2021) ISSN: 1097-4172 [Electronic] United States
PMID33836156 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2021 Elsevier Inc. All rights reserved.
Chemical References
  • Topoisomerase I Inhibitors
  • Topotecan
  • DNA Topoisomerases, Type I
  • TOP1 protein, human
Topics
  • Animals
  • COVID-19 (enzymology, pathology)
  • Chlorocebus aethiops
  • DNA Topoisomerases, Type I (metabolism)
  • Humans
  • Inflammation (drug therapy, enzymology, pathology, virology)
  • Mesocricetus
  • Mice
  • Mice, Transgenic
  • SARS-CoV-2 (metabolism)
  • THP-1 Cells
  • Topoisomerase I Inhibitors (pharmacology)
  • Topotecan (pharmacology)
  • Vero Cells
  • COVID-19 Drug Treatment

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: