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

2021; Cell Press; Volume: 184; Issue: 10 Linguagem: Inglês

10.1016/j.cell.2021.03.051

1097-4172

Jessica Ho, Bobo Wing-Yee Mok, Laura Campisi, Tristan X. Jordan, Soner Yildiz, Sreeja Parameswaran, Joseph A. Wayman, Natasha N. Gaudreault, David A. Meekins, Sabarish V. Indran, Igor Morozov, Jessie D. Trujillo, Yesai Fstkchyan, Raveen Rathnasinghe, Zeyu Zhu, Simin Zheng, Nan Zhao, Kris M. White, Helen Ray-Jones, Valeriya Malysheva, Michiel J. Thiecke, S. 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, André L. Moreira, Mariano Carossino, Udeni B. R. Balasuriya, Minji Byun, Randy A. Albrecht, Michael Schotsaert, Adolfo Garcı́a-Sastre, Sumit K. Chanda, Emily R. Miraldi, Anand D. Jeyasekharan, Benjamin R. tenOever, Mikhail Spivakov, Matthew T. Weirauch, Sven Heinz, Honglin Chen, Christopher Benner, Jüergen A. Richt, Ivan Marazzi,

Phagocytosis and Immune Regulation

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.