Author ORCID Identifier
Gomez, Teresa Allende Aydillo: 0000-0003-3086-1058
Liu, Wen-Chun: 0000-0003-0344-4371
Carossino, Mariano: 0000-0003-3864-5915
Rathnasinghe, Raveen: 0000-0002-1260-2493
Bakker, Jan: 0000-0003-2236-7391
Ho, Jessica Sook Yuin: 0000-0003-2234-2602
Byun, Minji: 0000-0002-2830-4079
Shum, Elaine: 0000-0002-0390-5716
Jordan, Tristan: 0000-0002-0602-2871
Yildiz, Soner: 0000-0002-7235-6108
Document Type
Article
Publication Date
2021
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.
Publication Source (Journal or Book title)
Cell
First Page
2618
Last Page
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Recommended Citation
Ho, J. S., Mok, B. W., Campisi, L., Jordan, T., Ho, J. S., Parameswaran, S., Wayman, J. A., Gaudreault, N. N., Meekins, D. A., Indran, S. V., Morozov, I., Trujillo, J. D., Fstkchyan, Y. S., Rathnasinghe, R., Zhu, Z. Y., Zheng, S. M., Zhao, N. M., White, K., Ray-Jones, H., Malysheva, V., Thiecke, M. J., Lau, S. Y., Liu, H. L., Zhang, A. N., Lee, S., Liu, W. C., Jangra, S., Escalera, A., Aydillo, T., Melo, B. S., Guccione, E., Sebra, R., Shum, E., & Bakker, J. (2021). Top1 Inhibition Therapy Protects Against Sars-Cov-2-Induced Lethal Inflammation. Cell, 184 (10), 2618-#ERROR!. https://doi.org/10.1016/j.cell.2021.03.051