Identification of novel anti-ZIKV drugs from viral-infection temporal gene expression profiles
Zika virus (ZIKV) infections are typically asymptomatic but cause severe neurological complications (e.g. Guillain-Barré syndrome in adults, and microcephaly in newborns). There are currently no specific therapy or vaccine options available to prevent ZIKV infections. Temporal gene expression profiles of ZIKV-infected human brain microvascular endothelial cells (HBMECs) were used in this study to identify genes essential for viral replication. These genes were then used to identify novel anti-ZIKV agents and validated in publicly available data and functional wet-lab experiments. Here, we found that ZIKV effectively evaded activation of immune response-related genes and completely reprogrammed cellular transcriptional architectures. Knockdown of genes, which gradually upregulated during viral infection but showed distinct expression patterns between ZIKV- and mock infection, discovered novel proviral and antiviral factors. One-third of the 74 drugs found through signature-based drug repositioning and cross-reference with the Drug Gene Interaction Database (DGIdb) were known anti-ZIKV agents. In cellular assays, two promising antiviral candidates (Luminespib/NVP-AUY922, L-161982) were found to reduce viral replication without causing cell toxicity. Overall, our time-series transcriptome-based methods offer a novel and feasible strategy for antiviral drug discovery. Our strategies, which combine conventional and data-driven analysis, can be extended for other pathogens causing pandemics in the future.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Emerging microbes & infections - 12(2023), 1 vom: 31. Dez., Seite 2174777 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Nailou [VerfasserIn] |
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| Links: |
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| Themen: |
Antiviral Agents |
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| Anmerkungen: |
Date Completed 23.02.2023 Date Revised 24.02.2023 published: Print Citation Status MEDLINE |
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| doi: |
10.1080/22221751.2023.2174777 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM352255706 |
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| 520 | |a Zika virus (ZIKV) infections are typically asymptomatic but cause severe neurological complications (e.g. Guillain-Barré syndrome in adults, and microcephaly in newborns). There are currently no specific therapy or vaccine options available to prevent ZIKV infections. Temporal gene expression profiles of ZIKV-infected human brain microvascular endothelial cells (HBMECs) were used in this study to identify genes essential for viral replication. These genes were then used to identify novel anti-ZIKV agents and validated in publicly available data and functional wet-lab experiments. Here, we found that ZIKV effectively evaded activation of immune response-related genes and completely reprogrammed cellular transcriptional architectures. Knockdown of genes, which gradually upregulated during viral infection but showed distinct expression patterns between ZIKV- and mock infection, discovered novel proviral and antiviral factors. One-third of the 74 drugs found through signature-based drug repositioning and cross-reference with the Drug Gene Interaction Database (DGIdb) were known anti-ZIKV agents. In cellular assays, two promising antiviral candidates (Luminespib/NVP-AUY922, L-161982) were found to reduce viral replication without causing cell toxicity. Overall, our time-series transcriptome-based methods offer a novel and feasible strategy for antiviral drug discovery. Our strategies, which combine conventional and data-driven analysis, can be extended for other pathogens causing pandemics in the future | ||
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| 700 | 1 | |a Tan, Zhongyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Jinbo |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Sai |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Miao, Yuanjiu |e verfasserin |4 aut | |
| 700 | 1 | |a Ding, Qingwen |e verfasserin |4 aut | |
| 700 | 1 | |a Yi, Wenfu |e verfasserin |4 aut | |
| 700 | 1 | |a Gan, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Chunjie |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Bin |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hanzhong |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Zhenhua |e verfasserin |4 aut | |
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