Luminescent reporter cells enable the identification of broad-spectrum antivirals against emerging viruses
© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC..
The emerging viruses SARS-CoV-2 and arenaviruses cause severe respiratory and hemorrhagic diseases, respectively. The production of infectious particles of both viruses and virus spread in tissues requires cleavage of surface glycoproteins (GPs) by host proprotein convertases (PCs). SARS-CoV-2 and arenaviruses rely on GP cleavage by PCs furin and subtilisin kexin isozyme-1/site-1 protease (SKI-1/S1P), respectively. We report improved luciferase-based reporter cell lines, named luminescent inducible proprotein convertase reporter cells that we employ to monitor PC activity in its authentic subcellular compartment. Using these sensor lines we screened a small compound library in high-throughput manner. We identified 23 FDA-approved small molecules, among them monensin which displayed broad activity against furin and SKI-1/S1P. Monensin inhibited arenaviruses and SARS-CoV-2 in a dose-dependent manner. We observed a strong reduction in infectious particle release upon monensin treatment with little effect on released genome copies. This was reflected by inhibition of SARS-CoV-2 spike processing suggesting the release of immature particles. In a proof of concept experiment using human precision cut lung slices, monensin potently inhibited SARS-CoV-2 infection, evidenced by reduced infectious particle release. We propose that our PC sensor pipeline is a suitable tool to identify broad-spectrum antivirals with therapeutic potential to combat current and future emerging viruses.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:95 |
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| Enthalten in: |
Journal of medical virology - 95(2023), 11 vom: 17. Nov., Seite e29211 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Löw, Karin [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 27.11.2023 Date Revised 08.12.2023 published: Print Citation Status MEDLINE |
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| doi: |
10.1002/jmv.29211 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM364668938 |
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| 245 | 1 | 0 | |a Luminescent reporter cells enable the identification of broad-spectrum antivirals against emerging viruses |
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| 520 | |a © 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC. | ||
| 520 | |a The emerging viruses SARS-CoV-2 and arenaviruses cause severe respiratory and hemorrhagic diseases, respectively. The production of infectious particles of both viruses and virus spread in tissues requires cleavage of surface glycoproteins (GPs) by host proprotein convertases (PCs). SARS-CoV-2 and arenaviruses rely on GP cleavage by PCs furin and subtilisin kexin isozyme-1/site-1 protease (SKI-1/S1P), respectively. We report improved luciferase-based reporter cell lines, named luminescent inducible proprotein convertase reporter cells that we employ to monitor PC activity in its authentic subcellular compartment. Using these sensor lines we screened a small compound library in high-throughput manner. We identified 23 FDA-approved small molecules, among them monensin which displayed broad activity against furin and SKI-1/S1P. Monensin inhibited arenaviruses and SARS-CoV-2 in a dose-dependent manner. We observed a strong reduction in infectious particle release upon monensin treatment with little effect on released genome copies. This was reflected by inhibition of SARS-CoV-2 spike processing suggesting the release of immature particles. In a proof of concept experiment using human precision cut lung slices, monensin potently inhibited SARS-CoV-2 infection, evidenced by reduced infectious particle release. We propose that our PC sensor pipeline is a suitable tool to identify broad-spectrum antivirals with therapeutic potential to combat current and future emerging viruses | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 650 | 4 | |a high-throughput screening | |
| 650 | 4 | |a inducible sensor cell lines | |
| 650 | 4 | |a inhibition | |
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| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 700 | 1 | |a Möller, Rebecca |e verfasserin |4 aut | |
| 700 | 1 | |a Stegmann, Cora |e verfasserin |4 aut | |
| 700 | 1 | |a Becker, Miriam |e verfasserin |4 aut | |
| 700 | 1 | |a Rehburg, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Obernolte, Helena |e verfasserin |4 aut | |
| 700 | 1 | |a Schaudien, Dirk |e verfasserin |4 aut | |
| 700 | 1 | |a Oestereich, Lisa |e verfasserin |4 aut | |
| 700 | 1 | |a Braun, Armin |e verfasserin |4 aut | |
| 700 | 1 | |a Kunz, Stefan |e verfasserin |4 aut | |
| 700 | 1 | |a Gerold, Gisa |e verfasserin |4 aut | |
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