There is an urgent need for effective antiviral drugs to alleviate the current COVID-19 pandemic. Here, we rationally designed and developed chimeric antisense oligonucleotides to degrade envelope and spike RNAs of SARS-CoV-2. Each oligonucleotide comprises a 3'antisense sequence for target recognition and a 5'-phosphorylated 2'-5' poly(A)₄ for guided ribonuclease L (RNase L) activation. Since RNase L can potently cleave single strand RNA during innate antiviral response, the improved degradation efficiency of chimeric oligonucleotides was twice as much as classic antisense oligonucleotides in Vero cells, for both SARS-CoV-2 RNA targets. In pseudovirus infection models, one of chimeric oligonucleotides targeting spike RNA achieved potent and universal inhibition of both SARS-CoV-2 and its recently reported N501Y and/or ΔH69/ΔV70 mutants. These results showed that the constructed chimeric oligonucleotides could efficiently degrade pathogenic RNA of SARS-CoV-2 facilitated by immune activation, showing promising potentials as antiviral nucleic acid drugs for COVID-19.

中文翻译：

---

使用嵌合反义寡核苷酸通过RNase L激活有效抑制SARS-CoV-2。

迫切需要有效的抗病毒药物来缓解当前的COVID-19大流行。在这里，我们合理地设计和开发了嵌合的反义寡核苷酸，以降解SARS-CoV-2的包膜和刺突RNA。每个寡核苷酸包含用于靶标识别的3'反义序列和5'-磷酸化的2'-5'poly（A）₄用于引导的核糖核酸酶L（RNase L）激活。由于RNase L可以在先天抗病毒应答过程中有效裂解单链RNA，因此，对于两个SARS-CoV-2 RNA靶标，嵌合寡核苷酸的改良降解效率是Vero细胞中经典反义寡核苷酸的两倍。在伪病毒感染模型中，靶向刺突RNA的嵌合寡核苷酸之一实现了SARS-CoV-2及其最近报道的N501Y和/或ΔH69/ΔV70突变体的有效抑制和普遍抑制。这些结果表明，所构建的嵌合寡核苷酸可以通过免疫活化而有效降解SARS-CoV-2的致病RNA，显示出作为COVID-19的抗病毒核酸药物的有希望的潜力。