A1 Refereed original research article in a scientific journal
Virus-specific Dicer-substrate siRNA swarms inhibit SARS-CoV-2 infection in TMPRSS2-expressing Vero E6 cells
Authors: Jiang, Miao; Laine, Larissa; Kolehmainen, Pekka; Kakkola, Laura; Avelin, Veera; Väisänen, Elina; Poranen, Minna M.; Österlund, Pamela; Julkunen, Ilkka
Publisher: Frontiers Media SA
Publication year: 2024
Journal: Frontiers in Microbiology
Journal name in source: Frontiers in Microbiology
Journal acronym: Front Microbiol
Volume: 15
eISSN: 1664-302X
DOI: https://doi.org/10.3389/fmicb.2024.1432349
Web address : https://doi.org/10.3389/fmicb.2024.1432349
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/477084217
After 4 years of the COVID-19 pandemic, SARS-CoV-2 continues to circulate with epidemic waves caused by evolving new variants. Although the rapid development of vaccines and approved antiviral drugs has reduced virus transmission and mitigated the symptoms of infection, the continuous emergence of new variants and the lack of simple-use (non-hospitalized, easy timing, local delivery, direct acting, and host-targeting) treatment modalities have limited the effectiveness of COVID-19 vaccines and drugs. Therefore, novel therapeutic approaches against SARS-CoV-2 infection are still urgently needed. As a positive-sense single-stranded RNA virus, SARS-CoV-2 is highly susceptible to RNA interference (RNAi). Accordingly, small interfering (si)RNAs targeting different regions of SARS-CoV-2 genome can effectively block the expression and replication of the virus. However, the rapid emergence of new SARS-CoV-2 variants with different genomic mutations has led to the problem of viral escape from the targets of RNAi strategy, which has increased the potential of off-target effects by siRNA and decreased the efficacy of long-term use of siRNA treatment. In our study, we enzymatically generated a set of Dicer-substrate (D)siRNA swarms containing DsiRNAs targeting single or multiple conserved sequences of SARS-CoV-2 genome by using in vitro transcription, replication and Dicer digestion system. Pre-transfection of these DsiRNA swarms into Vero E6-TMPRSS2 cells inhibited the replication of several SARS-CoV-2 variants, including the recent Omicron subvariants BQ.1.1 and XBB.1.5. This in vitro investigation of novel DsiRNA swarms provides solid evidence for the feasibility of this new RNAi strategy in the prevention and treatment of SARS-CoV-2 infection.
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Funding information in the publication:
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Academy of Finland (grant numbers 339512 to LK, 339511 to PÖ, 331627 to MP, and 336410 to IJ), the Jane and Aatos Erkko Foundation (grant numbers 3067-84b53 and 5360-cc2fc to IJ), and the Sigrid Juselius Foundation (to MP and IJ).
