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

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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.

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