Topoisomerase 1 inhibition therapy protects against SARS-CoV-2-induced inflammation and death in animal models.
Jessica Sook Yuin HoBobo Wing-Yee MokLaura CampisiTristan JordanSoner YildizSreeja ParameswaranJoseph A WaymanNatasha N GaudreaultDavid A MeekinsSabarish V IndranIgor MorozovJessie D TrujilloYesai S FstkchyanRaveen RathnasingheZeyu ZhuSimin ZhengNan ZhaoKris WhiteHelen Ray-JonesValeriya MalyshevaMichiel J ThieckeSiu-Ying LauHonglian LiuAnna Junxia ZhangAndrew Chak-Yiu LeeWen-Chun LiuTeresa A Aydillo GomezBetsaida Salom MeloErnesto GuccioneRobert SebraElaine ShumJan BakkerDavid A KaufmanAndre L MoreiraMariano CarossinoUdeni B R BalasuriyaMinji ByunEmily R MiraldiRandy A AlbrechtMichael SchotsaertAdolfo Garcia-SastreSumit K ChandaAnand D JeyasekharanBenjamin R TenOeverMikhail SpivakovMatthew T WeirauchSven HeinzHonglin ChenChristopher BennerJuergen A RichtIvan MarazziPublished in: bioRxiv : the preprint server for biology (2020)
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.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- coronavirus disease
- oxidative stress
- mouse model
- clinical trial
- diabetic rats
- high glucose
- gene expression
- cardiovascular events
- drug induced
- dna methylation
- type diabetes
- risk factors
- signaling pathway
- coronary artery disease
- mesenchymal stem cells
- endothelial cells
- stem cells
- transcription factor
- cardiovascular disease
- phase iii