Dicoumarol is an effective post-exposure prophylactic for SARS-CoV-2 Omicron infection in human airway epithelium.

Autor: Peng Y; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, China.; Department of Otolaryngology, Infectious Diseases Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Chen SY; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, China., Wang ZN; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, China., Zhou ZQ; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, China., Sun J; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, China., Zhang GA; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, China., Li J; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, China.; Guangzhou Laboratory, Guangzhou, China., Wang L; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, China.; Guangzhou Laboratory, Guangzhou, China., Zhao JC; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, China., Tang XX; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, China. tangxiaoxiao@gird.cn.; Guangzhou Laboratory, Guangzhou, China. tangxiaoxiao@gird.cn., Wang DY; Department of Otolaryngology, Infectious Diseases Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. entwdy@nus.edu.sg., Zhong NS; State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, China. nanshan@vip.163.com.; Guangzhou Laboratory, Guangzhou, China. nanshan@vip.163.com.
Jazyk: angličtina
Zdroj: Signal transduction and targeted therapy [Signal Transduct Target Ther] 2023 Jun 10; Vol. 8 (1), pp. 242. Date of Electronic Publication: 2023 Jun 10.
DOI: 10.1038/s41392-023-01511-7
Abstrakt: Repurposing existing drugs to inhibit SARS-CoV-2 infection in airway epithelial cells (AECs) is a quick way to find novel treatments for COVID-19. Computational screening has found dicoumarol (DCM), a natural anticoagulant, to be a potential SARS-CoV-2 inhibitor, but its inhibitory effects and possible working mechanisms remain unknown. Using air-liquid interface culture of primary human AECs, we demonstrated that DCM has potent antiviral activity against the infection of multiple Omicron variants (including BA.1, BQ.1 and XBB.1). Time-of-addition and drug withdrawal assays revealed that early treatment (continuously incubated after viral absorption) of DCM could markedly inhibit Omicron replication in AECs, but DCM did not affect the absorption, exocytosis and spread of viruses or directly eliminate viruses. Mechanistically, we performed single-cell sequencing analysis (a database of 77,969 cells from different airway locations from 10 healthy volunteers) and immunofluorescence staining, and showed that the expression of NAD(P)H quinone oxidoreductase 1 (NQO1), one of the known DCM targets, was predominantly localised in ciliated AECs. We further found that the NQO1 expression level was positively correlated with both the disease severity of COVID-19 patients and virus copy levels in cultured AECs. In addition, DCM treatment downregulated NQO1 expression and disrupted signalling pathways associated with SARS-CoV-2 disease outcomes (e.g., Endocytosis and COVID-19 signalling pathways) in cultured AECs. Collectively, we demonstrated that DCM is an effective post-exposure prophylactic for SARS-CoV-2 infection in the human AECs, and these findings could help physicians formulate novel treatment strategies for COVID-19.
(© 2023. The Author(s).)
Databáze: MEDLINE
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