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A siRNA targets and inhibits a broad range of SARS-CoV-2 infections including Delta variant

ABSTRACT: The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants has altered the trajectory of the COVID-19 pandemic and raised some uncertainty on long term efficiency of vaccine strategy. The development of new therapeutics against a wide range of SARS-CoV-2 variants is imperative. We here have designed an inhalable siRNA, C6G25S, which covers 99.8% of current SARS-CoV-2 variants and is capable of inhibiting dominant strains, including Alpha, Delta, Gamma and Epsilon, at picomolar ranges of IC50 in vitro. Moreover, C6G25S could completely inhibit the production of infectious virions in lungs by prophylactic treatment, and decrease 96.2% of virions by co-treatment in K18-hACE2-transgenic mice, accompanying with a significant prevention of virus-associated extensive pulmonary alveolar damage, vascular thrombi, and immune cell infiltrations. Our data suggests that C6G25S provides an alternative and effective approach to combating the COVID-19 pandemic.

SUBMITTER: Prof. Pan-Chyr Yang

PROVIDER: S-SCDT-EMM-2021-15298 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:BackgroundThe SARS-CoV-2 Delta variant was first identified in the U.S. in March 2021 and has rapidly become the predominant lineage across the U.S. due to increased transmissibility, immune evasion and vaccine breakthrough. The aim of this study was to better understand the genetic diversity and the potential impact of mutations observed in SARS-CoV-2 viruses circulating in the U.S. in vaccinated individuals.ResultsWhole genome sequencing was performed on thirty-four SARS-CoV-2 positive samples using the Oxford Nanopore MinION. Evolutionary genomic analysis revealed two novel mutations, ORF1b:V2354F and a premature stop codon, ORF7a:Q94*, identified in a cluster of SARS-CoV-2 Delta isolates collected from vaccinated individuals in Colorado. The ORF1b:V2354F mutation, corresponding to NSP15:V303F, may induce a conformational change and result in a disruption to a flanking beta-sheet structure. The premature stop codon, ORF7a:Q94*, truncates the transmembrane protein and cytosolic tail used to mediate protein transport. This may affect protein localization to the ER-Golgi. In addition to these novel mutations, the cluster of vaccinated isolates contain an additional mutation in the spike protein, at position 112, compared to the Delta variant defining mutations. This mutation, S112L, exists in isolates previously obtained in the U.S. The S112L mutation substitutes a bulky hydrophobic side chain for a polar side chain, which results in a non-conservative substitution within the protein that may affect antibody-binding affinity. Additionally, the vaccinated cluster of isolates contains non-synonymous mutations within ORF8 and NSPs which further distinguish this cluster from the respective ancestral Delta variant.ConclusionsThese results show there is an emerging sub-lineage of the ancestral Delta variant circulating in the U.S. As mutations emerge in constellations, those with a potentially beneficial advantage to the virus may continue to circulate while others will cease.

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A siRNA targets and inhibits a broad range of SARS-CoV-2 infections including Delta variant

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