From a genome-wide screen of RNAi molecules against SARS-CoV-2 to a validated broad-spectrum and potent prophylaxis
© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply..
Expanding the arsenal of prophylactic approaches against SARS-CoV-2 is of utmost importance, specifically those strategies that are resistant to antigenic drift in Spike. Here, we conducted a screen of over 16,000 RNAi triggers against the SARS-CoV-2 genome, using a massively parallel assay to identify hyper-potent siRNAs. We selected Ten candidates for in vitro validation and found five siRNAs that exhibited hyper-potent activity (IC50 < 20 pM) and strong blockade of infectivity in live-virus experiments. We further enhanced this activity by combinatorial pairing of the siRNA candidates and identified cocktails that were active against multiple types of variants of concern (VOC). We then examined over 2,000 possible mutations in the siRNA target sites by using saturation mutagenesis and confirmed broad protection of the leading cocktail against future variants. Finally, we demonstrated that intranasal administration of this siRNA cocktail effectively attenuates clinical signs and viral measures of disease in the gold-standard Syrian hamster model. Our results pave the way for the development of an additional layer of antiviral prophylaxis that is orthogonal to vaccines and monoclonal antibodies.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:6 |
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| Enthalten in: |
Communications biology - 6(2023), 1 vom: 16. März, Seite 277 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yogev, Ohad [VerfasserIn] |
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| Links: |
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| Themen: |
Journal Article |
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| Anmerkungen: |
Date Completed 05.04.2023 Date Revised 16.08.2023 published: Electronic UpdateOf: bioRxiv. 2022 Apr 12;:. - PMID 35441162 Citation Status MEDLINE |
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| doi: |
10.1038/s42003-023-04589-5 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM354340921 |
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| 245 | 1 | 0 | |a From a genome-wide screen of RNAi molecules against SARS-CoV-2 to a validated broad-spectrum and potent prophylaxis |
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| 500 | |a UpdateOf: bioRxiv. 2022 Apr 12;:. - PMID 35441162 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. | ||
| 520 | |a Expanding the arsenal of prophylactic approaches against SARS-CoV-2 is of utmost importance, specifically those strategies that are resistant to antigenic drift in Spike. Here, we conducted a screen of over 16,000 RNAi triggers against the SARS-CoV-2 genome, using a massively parallel assay to identify hyper-potent siRNAs. We selected Ten candidates for in vitro validation and found five siRNAs that exhibited hyper-potent activity (IC50 < 20 pM) and strong blockade of infectivity in live-virus experiments. We further enhanced this activity by combinatorial pairing of the siRNA candidates and identified cocktails that were active against multiple types of variants of concern (VOC). We then examined over 2,000 possible mutations in the siRNA target sites by using saturation mutagenesis and confirmed broad protection of the leading cocktail against future variants. Finally, we demonstrated that intranasal administration of this siRNA cocktail effectively attenuates clinical signs and viral measures of disease in the gold-standard Syrian hamster model. Our results pave the way for the development of an additional layer of antiviral prophylaxis that is orthogonal to vaccines and monoclonal antibodies | ||
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| 700 | 1 | |a Weissbrod, Omer |e verfasserin |4 aut | |
| 700 | 1 | |a Battistoni, Giorgia |e verfasserin |4 aut | |
| 700 | 1 | |a Bressan, Dario |e verfasserin |4 aut | |
| 700 | 1 | |a Naamati, Adi |e verfasserin |4 aut | |
| 700 | 1 | |a Falciatori, Ilaria |e verfasserin |4 aut | |
| 700 | 1 | |a Berkyurek, Ahmet Can |e verfasserin |4 aut | |
| 700 | 1 | |a Rasnic, Roni |e verfasserin |4 aut | |
| 700 | 1 | |a Izuagbe, Rhys |e verfasserin |4 aut | |
| 700 | 1 | |a Hosmillo, Myra |e verfasserin |4 aut | |
| 700 | 1 | |a Ilan, Shaul |e verfasserin |4 aut | |
| 700 | 1 | |a Grossman, Iris |e verfasserin |4 aut | |
| 700 | 1 | |a McCormick, Lauren |e verfasserin |4 aut | |
| 700 | 1 | |a Honeycutt, Christopher Cole |e verfasserin |4 aut | |
| 700 | 1 | |a Johnston, Timothy |e verfasserin |4 aut | |
| 700 | 1 | |a Gagne, Matthew |e verfasserin |4 aut | |
| 700 | 1 | |a Douek, Daniel C |e verfasserin |4 aut | |
| 700 | 1 | |a Goodfellow, Ian |e verfasserin |4 aut | |
| 700 | 1 | |a Hannon, Gregory James |e verfasserin |4 aut | |
| 700 | 1 | |a Erlich, Yaniv |e verfasserin |4 aut | |
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