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

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), 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.

• Authors: Jessica 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, 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, Emily R Miraldi, Randy A Albrecht, Michael Schotsaert, Adolfo Garcia-Sastre, Sumit K Chanda, Anand D Jeyasekharan, Benjamin R TenOever, Mikhail Spivakov, Matthew T Weirauch, Sven Heinz, Honglin Chen, Christopher Benner, Juergen A Richt, Ivan Marazzi
• Journal: bioRxiv : the preprint server for biology (bioRxiv) (Dec 01 2020) United States
• PMID: 33299999 (Publication Type: Preprint)