Topoisomerase 1 inhibition therapy protects against SARS-CoV-2-induced inflammation and death in animal models

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 diseas...

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Published inbioRxiv
Main Authors Yuin Ho, Jessica Sook, Wing-Yee Mok, Bobo, Campisi, Laura, Jordan, Tristan, Yildiz, Soner, Parameswaran, Sreeja, Wayman, Joseph A, Gaudreault, Natasha N, Meekins, David A, Indran, Sabarish V, Morozov, Igor, Trujillo, Jessie D, Fstkchyan, Yesai S, Rathnasinghe, Raveen, Zhu, Zeyu, Zheng, Simin, Zhao, Nan, White, Kris, Ray-Jones, Helen, Malysheva, Valeriya, Thiecke, Michiel J, Lau, Siu-Ying, Liu, Honglian, Junxia Zhang, Anna, Chak-Yiu Lee, Andrew, Liu, Wen-Chun, Aydillo, Teresa, Salom Melo, Betsaida, Guccione, Ernesto, Sebra, Robert, Shum, Elaine, Bakker, Jan, Kaufman, David A, Moreira, Andre L, Carossino, Mariano, Balasuriya, Udeni B R, Byun, Minji, Miraldi, Emily R, Albrecht, Randy A, Schotsaert, Michael, Garcia-Sastre, Adolfo, Chanda, Sumit K, Jeyasekharan, Anand D, TenOever, Benjamin R, Spivakov, Mikhail, Weirauch, Matthew T, Heinz, Sven, Chen, Honglin, Benner, Christopher, Richt, Juergen A, Marazzi, Ivan
Format Journal Article Paper
LanguageEnglish
Published United States Cold Spring Harbor Laboratory Press 01.12.2020
Subjects
Animal models
Clinical trials
COVID-19
Infections
Inflammation
Morbidity
Rodents
Severe acute respiratory syndrome coronavirus 2
Topotecan
Transgenic mice
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Summary: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, and analyses, we report that Topoisomerase 1 (Top1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of Topotecan (TPT), a FDA-approved Top1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as four 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 COVID-19 in humans.
DOI:10.1101/2020.12.01.404483