Department of Chemistry, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377, Munich, Germany.
Max von Pettenkofer Institute and Gene Center, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 25, 81377, Munich, Germany.
Angew Chem Int Ed Engl. 2022 Sep 19;61(38):e202204556. doi: 10.1002/anie.202204556. Epub 2022 Aug 12.
The emergence of more transmissible or aggressive variants of SARS-CoV-2 requires the development of antiviral medication that is quickly adjustable to evolving viral escape mutations. Here we report the synthesis of chemically stabilized small interfering RNA (siRNA) against SARS-CoV-2. The siRNA can be further modified with receptor ligands such as peptides using Cu -catalysed click-chemistry. We demonstrate that optimized siRNAs can reduce viral loads and virus-induced cytotoxicity by up to five orders of magnitude in cell lines challenged with SARS-CoV-2. Furthermore, we show that an ACE2-binding peptide-conjugated siRNA is able to reduce virus replication and virus-induced apoptosis in 3D mucociliary lung microtissues. The adjustment of the siRNA sequence allows a rapid adaptation of their antiviral activity against different variants of concern. The ability to conjugate the siRNA via click-chemistry to receptor ligands facilitates the construction of targeted siRNAs for a flexible antiviral defence strategy.
SARS-CoV-2 更具传染性或侵袭性变异株的出现，需要开发能够快速适应病毒逃逸突变的抗病毒药物。在这里，我们报告了针对 SARS-CoV-2 的化学稳定小干扰 RNA（siRNA）的合成。可以使用铜催化的点击化学将受体配体（如肽）进一步修饰到 siRNA 上。我们证明，经优化的 siRNA 可将细胞系中受到 SARS-CoV-2 攻击时的病毒载量和病毒诱导的细胞毒性降低多达五个数量级。此外，我们还表明，一种 ACE2 结合肽偶联的 siRNA 能够降低 3D 黏液纤毛肺微组织中的病毒复制和病毒诱导的细胞凋亡。通过调整 siRNA 序列，可以快速适应其针对不同关注变异株的抗病毒活性。通过点击化学将 siRNA 与受体配体偶联的能力，为灵活的抗病毒防御策略提供了构建靶向 siRNA 的可能性。
