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Cell
. 2021 Mar 30;S0092-8674(21)00382-2.
doi: 10.1016/j.cell.2021.03.051. Online ahead of print.
TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation
Jessica Sook Yuin Ho 1 , Bobo Wing-Yee Mok 2 , Laura Campisi 1 , Tristan Jordan 1 , Soner Yildiz 1 , Sreeja Parameswaran 3 , Joseph A Wayman 4 , Natasha N Gaudreault 5 , David A Meekins 5 , Sabarish V Indran 5 , Igor Morozov 5 , Jessie D Trujillo 5 , Yesai S Fstkchyan 1 , Raveen Rathnasinghe 1 , Zeyu Zhu 1 , Simin Zheng 1 , Nan Zhao 1 , Kris White 1 , Helen Ray-Jones 6 , Valeriya Malysheva 6 , Michiel J Thiecke 7 , Siu-Ying Lau 2 , Honglian Liu 2 , Anna Junxia Zhang 2 , Andrew Chak-Yiu Lee 2 , Wen-Chun Liu 1 , Sonia Jangra 1 , Alba Escalera 1 , Teresa Aydillo 1 , Betsaida Salom Melo 8 , Ernesto Guccione 9 , Robert Sebra 10 , Elaine Shum 11 , Jan Bakker 12 , David A Kaufman 13 , Andre L Moreira 14 , Mariano Carossino 15 , Udeni B R Balasuriya 15 , Minji Byun 16 , Randy A Albrecht 17 , Michael Schotsaert 17 , Adolfo Garcia-Sastre 18 , Sumit K Chanda 19 , Emily R Miraldi 4 , Anand D Jeyasekharan 20 , Benjamin R TenOever 21 , Mikhail Spivakov 6 , Matthew T Weirauch 22 , Sven Heinz 23 , Honglin Chen 2 , Christopher Benner 23 , Juergen A Richt 24 , Ivan Marazzi 25
Affiliations
- PMID: 33836156
- PMCID: PMC8008343
- DOI: 10.1016/j.cell.2021.03.051
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.
Keywords: COVID-19; SARS-CoV-2; chromatin; cytokine storm; epigenetics; inducible genes; inflammation; topoisomerase; topotecan; transcription.