Efficient Inhibition of SARS-CoV-2 Using Chimeric Antisense Oligonucleotides through RNase L Activation*.

There is an urgent need to develop antiviral drugs and alleviate the current COVID-19 pandemic. Herein we report the design and construction of chimeric oligonucleotides comprising a 2'-OMe-modified antisense oligonucleotide and a 5'-phosphorylated 2'-5' poly(A)4 (4A2-5 ) to degrade envelope and spike RNAs of SARS-CoV-2. The oligonucleotide was used for ...
searching and recognizing target viral RNA sequence, and the conjugated 4A2-5 was used for guided RNase L activation to sequence-specifically degrade viral RNAs. Since RNase L can potently cleave single-stranded RNA during innate antiviral response, degradation efficiencies with these chimeras were twice as much as those with only antisense oligonucleotides for both SARS-CoV-2 RNA targets. In pseudovirus infection models, chimera-S4 achieved potent and broad-spectrum inhibition of SARS-CoV-2 and its N501Y and/or ?H69/?V70 mutants, indicating a promising antiviral agent based on the nucleic acid-hydrolysis targeting chimera (NATAC) strategy.
Mesh Terms:
Animals, Antiviral Agents, Chlorocebus aethiops, Coronavirus Envelope Proteins, Drug Design, Endoribonucleases, Enzyme Activation, HEK293 Cells, Humans, Hydrolysis, Microbial Sensitivity Tests, Mutation, Oligonucleotides, Antisense, RNA, Viral, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Vero Cells
Angew Chem Int Ed Engl
Date: Sep. 27, 2021
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