From a genome-wide screen of RNAi molecules against SARS-CoV-2 to a validated broad-spectrum and potent prophylaxis.

TitleFrom a genome-wide screen of RNAi molecules against SARS-CoV-2 to a validated broad-spectrum and potent prophylaxis.
Publication TypeJournal Article
Year of Publication2023
AuthorsYogev O, Weissbrod O, Battistoni G, Bressan D, Naamati A, Falciatori I, Berkyurek ACan, Rasnic R, Izuagbe R, Hosmillo M, Ilan S, Grossman I, McCormick L, Honeycutt CCole, Johnston T, Gagne M, Douek DC, Goodfellow I, Hannon GJames, Erlich Y
JournalCommun Biol
Volume6
Issue1
Pagination277
Date Published2023 Mar 16
ISSN2399-3642
KeywordsAdministration, Intranasal, Animals, COVID-19, Cricetinae, Mesocricetus, RNA Interference, RNA, Small Interfering, SARS-CoV-2
Abstract

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.

DOI10.1038/s42003-023-04589-5
Alternate JournalCommun Biol
PubMed ID36928598
PubMed Central IDPMC10019795
Grant ListMR/W005611/1 / MRC_ / Medical Research Council / United Kingdom

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