tetano
Editor, Senior Moderator
Cell
. 2021 Mar 30;S0092-8674(21)00382-2.
doi: 10.1016/j.cell.2021.03.051. Online ahead of print.
TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation
Jessica Sook Yuin Ho[SUP] 1 [/SUP], Bobo Wing-Yee Mok[SUP] 2 [/SUP], Laura Campisi[SUP] 1 [/SUP], Tristan Jordan[SUP] 1 [/SUP], Soner Yildiz[SUP] 1 [/SUP], Sreeja Parameswaran[SUP] 3 [/SUP], Joseph A Wayman[SUP] 4 [/SUP], Natasha N Gaudreault[SUP] 5 [/SUP], David A Meekins[SUP] 5 [/SUP], Sabarish V Indran[SUP] 5 [/SUP], Igor Morozov[SUP] 5 [/SUP], Jessie D Trujillo[SUP] 5 [/SUP], Yesai S Fstkchyan[SUP] 1 [/SUP], Raveen Rathnasinghe[SUP] 1 [/SUP], Zeyu Zhu[SUP] 1 [/SUP], Simin Zheng[SUP] 1 [/SUP], Nan Zhao[SUP] 1 [/SUP], Kris White[SUP] 1 [/SUP], Helen Ray-Jones[SUP] 6 [/SUP], Valeriya Malysheva[SUP] 6 [/SUP], Michiel J Thiecke[SUP] 7 [/SUP], Siu-Ying Lau[SUP] 2 [/SUP], Honglian Liu[SUP] 2 [/SUP], Anna Junxia Zhang[SUP] 2 [/SUP], Andrew Chak-Yiu Lee[SUP] 2 [/SUP], Wen-Chun Liu[SUP] 1 [/SUP], Sonia Jangra[SUP] 1 [/SUP], Alba Escalera[SUP] 1 [/SUP], Teresa Aydillo[SUP] 1 [/SUP], Betsaida Salom Melo[SUP] 8 [/SUP], Ernesto Guccione[SUP] 9 [/SUP], Robert Sebra[SUP] 10 [/SUP], Elaine Shum[SUP] 11 [/SUP], Jan Bakker[SUP] 12 [/SUP], David A Kaufman[SUP] 13 [/SUP], Andre L Moreira[SUP] 14 [/SUP], Mariano Carossino[SUP] 15 [/SUP], Udeni B R Balasuriya[SUP] 15 [/SUP], Minji Byun[SUP] 16 [/SUP], Randy A Albrecht[SUP] 17 [/SUP], Michael Schotsaert[SUP] 17 [/SUP], Adolfo Garcia-Sastre[SUP] 18 [/SUP], Sumit K Chanda[SUP] 19 [/SUP], Emily R Miraldi[SUP] 4 [/SUP], Anand D Jeyasekharan[SUP] 20 [/SUP], Benjamin R TenOever[SUP] 21 [/SUP], Mikhail Spivakov[SUP] 6 [/SUP], Matthew T Weirauch[SUP] 22 [/SUP], Sven Heinz[SUP] 23 [/SUP], Honglin Chen[SUP] 2 [/SUP], Christopher Benner[SUP] 23 [/SUP], Juergen A Richt[SUP] 24 [/SUP], Ivan Marazzi[SUP] 25 [/SUP]
Affiliations
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), 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.
Keywords: COVID-19; SARS-CoV-2; chromatin; cytokine storm; epigenetics; inducible genes; inflammation; topoisomerase; topotecan; transcription.
. 2021 Mar 30;S0092-8674(21)00382-2.
doi: 10.1016/j.cell.2021.03.051. Online ahead of print.
TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation
Jessica Sook Yuin Ho[SUP] 1 [/SUP], Bobo Wing-Yee Mok[SUP] 2 [/SUP], Laura Campisi[SUP] 1 [/SUP], Tristan Jordan[SUP] 1 [/SUP], Soner Yildiz[SUP] 1 [/SUP], Sreeja Parameswaran[SUP] 3 [/SUP], Joseph A Wayman[SUP] 4 [/SUP], Natasha N Gaudreault[SUP] 5 [/SUP], David A Meekins[SUP] 5 [/SUP], Sabarish V Indran[SUP] 5 [/SUP], Igor Morozov[SUP] 5 [/SUP], Jessie D Trujillo[SUP] 5 [/SUP], Yesai S Fstkchyan[SUP] 1 [/SUP], Raveen Rathnasinghe[SUP] 1 [/SUP], Zeyu Zhu[SUP] 1 [/SUP], Simin Zheng[SUP] 1 [/SUP], Nan Zhao[SUP] 1 [/SUP], Kris White[SUP] 1 [/SUP], Helen Ray-Jones[SUP] 6 [/SUP], Valeriya Malysheva[SUP] 6 [/SUP], Michiel J Thiecke[SUP] 7 [/SUP], Siu-Ying Lau[SUP] 2 [/SUP], Honglian Liu[SUP] 2 [/SUP], Anna Junxia Zhang[SUP] 2 [/SUP], Andrew Chak-Yiu Lee[SUP] 2 [/SUP], Wen-Chun Liu[SUP] 1 [/SUP], Sonia Jangra[SUP] 1 [/SUP], Alba Escalera[SUP] 1 [/SUP], Teresa Aydillo[SUP] 1 [/SUP], Betsaida Salom Melo[SUP] 8 [/SUP], Ernesto Guccione[SUP] 9 [/SUP], Robert Sebra[SUP] 10 [/SUP], Elaine Shum[SUP] 11 [/SUP], Jan Bakker[SUP] 12 [/SUP], David A Kaufman[SUP] 13 [/SUP], Andre L Moreira[SUP] 14 [/SUP], Mariano Carossino[SUP] 15 [/SUP], Udeni B R Balasuriya[SUP] 15 [/SUP], Minji Byun[SUP] 16 [/SUP], Randy A Albrecht[SUP] 17 [/SUP], Michael Schotsaert[SUP] 17 [/SUP], Adolfo Garcia-Sastre[SUP] 18 [/SUP], Sumit K Chanda[SUP] 19 [/SUP], Emily R Miraldi[SUP] 4 [/SUP], Anand D Jeyasekharan[SUP] 20 [/SUP], Benjamin R TenOever[SUP] 21 [/SUP], Mikhail Spivakov[SUP] 6 [/SUP], Matthew T Weirauch[SUP] 22 [/SUP], Sven Heinz[SUP] 23 [/SUP], Honglin Chen[SUP] 2 [/SUP], Christopher Benner[SUP] 23 [/SUP], Juergen A Richt[SUP] 24 [/SUP], Ivan Marazzi[SUP] 25 [/SUP]
Affiliations
- PMID: 33836156
- PMCID: PMC8008343
- DOI: 10.1016/j.cell.2021.03.051
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), 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.
Keywords: COVID-19; SARS-CoV-2; chromatin; cytokine storm; epigenetics; inducible genes; inflammation; topoisomerase; topotecan; transcription.