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10.1016/j.cell.2021.03.051

http://scihub22266oqcxt.onion/10.1016/j.cell.2021.03.051
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suck abstract from ncbi


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pmid33836156      Cell 2021 ; 184 (10): 2618-2632.e17
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  • TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation #MMPMID33836156
  • Ho JSY; Mok BW; Campisi L; Jordan T; Yildiz S; Parameswaran S; Wayman JA; Gaudreault NN; Meekins DA; Indran SV; Morozov I; Trujillo JD; Fstkchyan YS; Rathnasinghe R; Zhu Z; Zheng S; Zhao N; White K; Ray-Jones H; Malysheva V; Thiecke MJ; Lau SY; Liu H; Zhang AJ; Lee AC; Liu WC; Jangra S; Escalera A; Aydillo T; Melo BS; Guccione E; Sebra R; Shum E; Bakker J; Kaufman DA; Moreira AL; Carossino M; Balasuriya UBR; Byun M; Albrecht RA; Schotsaert M; Garcia-Sastre A; Chanda SK; Miraldi ER; Jeyasekharan AD; TenOever BR; Spivakov M; Weirauch MT; Heinz S; Chen H; Benner C; Richt JA; Marazzi I
  • Cell 2021[May]; 184 (10): 2618-2632.e17 PMID33836156show ga
  • 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.
  • |*COVID-19 Drug Treatment[MESH]
  • |Animals[MESH]
  • |COVID-19/enzymology/pathology[MESH]
  • |Chlorocebus aethiops[MESH]
  • |DNA Topoisomerases, Type I/*metabolism[MESH]
  • |Humans[MESH]
  • |Inflammation/drug therapy/enzymology/pathology/virology[MESH]
  • |Mesocricetus[MESH]
  • |Mice[MESH]
  • |Mice, Transgenic[MESH]
  • |SARS-CoV-2/*metabolism[MESH]
  • |THP-1 Cells[MESH]
  • |Topoisomerase I Inhibitors/*pharmacology[MESH]
  • |Topotecan/*pharmacology[MESH]


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