Inhibition of SARS-CoV-2 Variants by Broad-Spectrum Antisense Oligonucleotides Targeting the Highly Conserved 3C-like protease
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The emergence of drug-resistant SARS-CoV-2 variants underscores the urgent need for broad-spectrum antiviral strategies. This study aimed to design and screen antisense oligonucleotides (ASOs) targeting the highly conserved 3C-like protease (3CLpro) of SARS-CoV-2. Using RNAstructure v6.3 and OligoWalk, we designed ASOs based on secondary structure and thermodynamic stability. Among the candidates, 3CLp-4 demonstrated potent mRNA knockdown in 293T cells and significantly inhibited viral replication in a SARS-CoV-2 replicon system. In live virus infection models, 3CLp-4 effectively reduced viral RNA load and titers of the SARS-CoV-2 Wuhan-Hu-1, Delta, Omicron, and XBB.1.1.6 variants. These results highlight the broad-spectrum antiviral activity of 3CLp-4, supporting its potential as a resistance-resistant therapeutic agent against evolving SARS-CoV-2 variants.
