Genome wide screen of RNAi molecules against SARS-CoV-2 creates a broadly potent prophylaxis.

Publication Type	Preprint
Authors	Yogev O, Weissbrod O, Battistoni G, Bressan D, Naamti A, Falciatori I, Berkyurek A, Rasnic R, Hosmillo M, Ilan S, Grossman I, McCormick L, Honeycutt C, Johnston T, Gagne M, Douek D, Goodfellow I, Hannon G, Erlich Y
Journal	bioRxiv
Date Published	04/12/2022
ISSN	2692-8205
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 with over 16,000 RNAi triggers against the SARS-CoV-2 genome using a massively parallel assay to identify hyper-potent siRNAs. We selected 10 candidates for in vitro validation and found five siRNAs that exhibited hyper-potent activity with IC50<20pM and strong neutralisation in live virus experiments. We further enhanced the activity by combinatorial pairing of the siRNA candidates to develop siRNA cocktails and found that these cocktails are active against multiple types of variants of concern (VOC). We examined over 2,000 possible mutations to the siRNA target sites using saturation mutagenesis and identified broad protection against future variants. Finally, we demonstrated that intranasal administration of the siRNA cocktail effectively attenuates clinical signs and viral measures of disease in the Syrian hamster model. Our results pave the way to development of an additional layer of antiviral prophylaxis that is orthogonal to vaccines and monoclonal antibodies.
DOI	10.1101/2022.04.12.488010
PubMed ID	35441162
PubMed Central ID	PMC9016640