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

Ho, J. S. Y.; Mok, B. W.-Y.; Campisi, L.; Jordan, T.; Yildiz, 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.; Zheng, S.; Zhao, N.; White, K.; Ray-Jones, H.; Malysheva, V.; Thiecke, M. J.; Lau, S.-Y.; Liu, H.; Zhang, A. J.; Lee, A. C.-Y.; Liu, W.-C.; Aydillo, T.; Melo, B. S.; Guccione, E.; Sebra, R.; Shum, E.; Bakker, J.; Kaufman, D. A.; Moreira, A.; Carossino, M.; Balasuriya, U. B. R.; Byun, M.; Miraldi, E. R.; Albrecht, R. A.; Schotsaert, M.; Garcia-Sastre, A.; Chanda, S. K.; Jeya

doi:10.1101/2020.12.01.404483

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bioRxiv · 10.1101/2020.12.01.404483

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

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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.

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Ho, J. S. Y., Mok, B. W.-Y., Campisi, L., Jordan, T., Yildiz, 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., Zheng, S., Zhao, N., White, K., Ray-Jones, H., Malysheva, V., Thiecke, M. J., Lau, S.-Y., Liu, H., Zhang, A. J., Lee, A. C.-Y., Liu, W.-C., Aydillo, T., Melo, B. S., Guccione, E., Sebra, R., Shum, E., Bakker, J., Kaufman, D. A., Moreira, A., Carossino, M., Balasuriya, U. B. R., Byun, M., Miraldi, E. R., Albrecht, R. A., Schotsaert, M., Garcia-Sastre, A., Chanda, S. K., Jeya. 2020-12-01. Topoisomerase 1 inhibition therapy protects against SARS-CoV-2-induced inflammation and death in animal models.. https://doi.org/10.1101/2020.12.01.404483

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