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Article: TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation

TitleTOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation
Authors
Keywordsinflammation
topoisomerase
chromatin
COVID-19
SARS-CoV-2
Issue Date2021
PublisherCell Press. The Journal's web site is located at http://www.elsevier.com/locate/cell
Citation
Cell, 2021, v. 184 n. 10, p. 2618-2632.e17 How to Cite?
AbstractThe 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.
Persistent Identifierhttp://hdl.handle.net/10722/308390
ISSN
2023 Impact Factor: 45.5
2023 SCImago Journal Rankings: 24.342
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHo, JSY-
dc.contributor.authorMok, BWY-
dc.contributor.authorCampisi, L-
dc.contributor.authorJordan, T-
dc.contributor.authorYildiz, S-
dc.contributor.authorParameswaran, S-
dc.contributor.authorWayman, JA-
dc.contributor.authorGaudreault, NN-
dc.contributor.authorMeekins, DA-
dc.contributor.authorIndran, SV-
dc.contributor.authorMorozov, I-
dc.contributor.authorTrujillo, JD-
dc.contributor.authorFstkchyan, YS-
dc.contributor.authorRathnasinghe, R-
dc.contributor.authorZhu, Z-
dc.contributor.authorZheng, S-
dc.contributor.authorZhao, N-
dc.contributor.authorWhite, K-
dc.contributor.authorRay-Jones, H-
dc.contributor.authorMalysheva, V-
dc.contributor.authorThiecke, MJ-
dc.contributor.authorLau, SY-
dc.contributor.authorLiu, H-
dc.contributor.authorZhang, AJ-
dc.contributor.authorLee, ACY-
dc.contributor.authorLiu, WC-
dc.contributor.authorJangra, S-
dc.contributor.authorEscalera, A-
dc.contributor.authorAydillo, T-
dc.contributor.authorMelo, BS-
dc.contributor.authorGuccione, E-
dc.contributor.authorSebra, R-
dc.contributor.authorShum, E-
dc.contributor.authorBakker, J-
dc.contributor.authorKaufman, DA-
dc.contributor.authorMoreira, AL-
dc.contributor.authorCarossino, M-
dc.contributor.authorBalasuriya, UBR-
dc.contributor.authorByun, M-
dc.contributor.authorAlbrecht, RA-
dc.contributor.authorSchotsaert, M-
dc.contributor.authorGarcia-Sastre, A-
dc.contributor.authorChanda, SK-
dc.contributor.authorMiraldi, ER-
dc.contributor.authorJeyasekharan, AD-
dc.contributor.authorTenOever, BR-
dc.contributor.authorSpivakov, M-
dc.contributor.authorWeirauch, MT-
dc.contributor.authorHeinz, S-
dc.contributor.authorChen, H-
dc.contributor.authorBenner, C-
dc.contributor.authorRicht, JA-
dc.contributor.authorMarazzi, I-
dc.date.accessioned2021-12-01T07:52:42Z-
dc.date.available2021-12-01T07:52:42Z-
dc.date.issued2021-
dc.identifier.citationCell, 2021, v. 184 n. 10, p. 2618-2632.e17-
dc.identifier.issn0092-8674-
dc.identifier.urihttp://hdl.handle.net/10722/308390-
dc.description.abstractThe 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.-
dc.languageeng-
dc.publisherCell Press. The Journal's web site is located at http://www.elsevier.com/locate/cell-
dc.relation.ispartofCell-
dc.subjectinflammation-
dc.subjecttopoisomerase-
dc.subjectchromatin-
dc.subjectCOVID-19-
dc.subjectSARS-CoV-2-
dc.titleTOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation-
dc.typeArticle-
dc.identifier.emailMok, BWY: bobomok@hku.hk-
dc.identifier.emailZhang, AJ: zhangajx@hkucc.hku.hk-
dc.identifier.emailLee, ACY: cyalee@hku.hk-
dc.identifier.emailChen, H: hlchen@hku.hk-
dc.identifier.authorityZhang, AJ=rp00413-
dc.identifier.authorityChen, H=rp00383-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1016/j.cell.2021.03.051-
dc.identifier.pmid33836156-
dc.identifier.pmcidPMC8008343-
dc.identifier.scopuseid_2-s2.0-85103985781-
dc.identifier.hkuros330650-
dc.identifier.volume184-
dc.identifier.issue10-
dc.identifier.spage2618-
dc.identifier.epage2632.e17-
dc.identifier.isiWOS:000652830800009-
dc.publisher.placeUnited States-

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