Identifying Inhibitors of -1 Programmed Ribosomal Frameshifting in a Broad Spectrum of Coronaviruses
Recurrent outbreaks of novel zoonotic coronavirus (CoV) diseases in recent years have highlighted the importance of developing therapeutics with broad-spectrum activity against CoVs. Because all CoVs use -1 programmed ribosomal frameshifting (-1 PRF) to control expression of key viral proteins, the frameshift signal in viral mRNA that stimulates -1 PRF provides a promising potential target for such therapeutics. To test the viability of this strategy, we explored whether small-molecule inhibitors of -1 PRF in SARS-CoV-2 also inhibited -1 PRF in a range of bat CoVs-the most likely source of future zoonoses. Six inhibitors identified in new and previous screens against SARS-CoV-2 were evaluated against the frameshift signals from a panel of representative bat CoVs as well as MERS-CoV. Some drugs had strong activity against subsets of these CoV-derived frameshift signals, while having limited to no effect on -1 PRF caused by frameshift signals from other viruses used as negative controls. Notably, the serine protease inhibitor nafamostat suppressed -1 PRF significantly for multiple CoV-derived frameshift signals. These results suggest it is possible to find small-molecule ligands that inhibit -1 PRF specifically in a broad spectrum of CoVs, establishing frameshift signals as a viable target for developing pan-coronaviral therapeutics.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Viruses - 14(2022), 2 vom: 18. Jan. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Munshi, Sneha [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.03.2022 Date Revised 03.08.2022 published: Electronic CommentIn: Viruses. 2022 Jul 13;14(7):. - PMID 35891506 Citation Status MEDLINE |
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| doi: |
10.3390/v14020177 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM337472785 |
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| 500 | |a CommentIn: Viruses. 2022 Jul 13;14(7):. - PMID 35891506 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Recurrent outbreaks of novel zoonotic coronavirus (CoV) diseases in recent years have highlighted the importance of developing therapeutics with broad-spectrum activity against CoVs. Because all CoVs use -1 programmed ribosomal frameshifting (-1 PRF) to control expression of key viral proteins, the frameshift signal in viral mRNA that stimulates -1 PRF provides a promising potential target for such therapeutics. To test the viability of this strategy, we explored whether small-molecule inhibitors of -1 PRF in SARS-CoV-2 also inhibited -1 PRF in a range of bat CoVs-the most likely source of future zoonoses. Six inhibitors identified in new and previous screens against SARS-CoV-2 were evaluated against the frameshift signals from a panel of representative bat CoVs as well as MERS-CoV. Some drugs had strong activity against subsets of these CoV-derived frameshift signals, while having limited to no effect on -1 PRF caused by frameshift signals from other viruses used as negative controls. Notably, the serine protease inhibitor nafamostat suppressed -1 PRF significantly for multiple CoV-derived frameshift signals. These results suggest it is possible to find small-molecule ligands that inhibit -1 PRF specifically in a broad spectrum of CoVs, establishing frameshift signals as a viable target for developing pan-coronaviral therapeutics | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Ileperuma, Sandaru M |e verfasserin |4 aut | |
| 700 | 1 | |a Halma, Matthew T J |e verfasserin |4 aut | |
| 700 | 1 | |a Kelly, Jamie A |e verfasserin |4 aut | |
| 700 | 1 | |a Halpern, Clarissa F |e verfasserin |4 aut | |
| 700 | 1 | |a Dinman, Jonathan D |e verfasserin |4 aut | |
| 700 | 1 | |a Loerch, Sarah |e verfasserin |4 aut | |
| 700 | 1 | |a Woodside, Michael T |e verfasserin |4 aut | |
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