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

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; Zhang, Anna Junxia; Chak-Yiu Lee, Andrew; Liu, Wen-Chun; Jangra, Sonia; Escalera, Alba; Aydillo, Teresa; Melo, Betsaida Salom; Guccione, Ernesto; Sebra, Robert; Shum, Elaine; Bakker, Jan; Kaufman, David A.; Moreira, Andre L.; Carossino, Mariano; Balasuriya, Udeni B.R.; Byun, Minji; Albrecht, Randy A.; Schotsaert, Michael; Garcia-Sastre, Adolfo; Chanda, Sumit K.; Miraldi, Emily R.; Jeyasekharan, Anand D.; TenOever, Benjamin R.; Spivakov, Mikhail; Weirauch, Matthew T.; Heinz, Sven; Chen, Honglin; Benner, Christopher; Richt, Juergen A.; Marazzi, Ivan

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 severe COVID-19 in humans.