Suppression of SARS-CoV-2 Replication with Stabilized and Click-Chemistry Modified siRNAs

Traube, Franziska R.; Stern, Marcel; Tölke, Annika J.; Rudelius, Martina; Mejias-Perez, Ernesto; Raddaoui, Nada; Kümmerer, Beate M.; Douat, Celine; Streshnev, Filipp; Albanese, Manuel; Wratil, Paul R.; Gärtner, Yasmin; Nainyte, Milda; Giorgio, Grazia; Michalakis, Stylianos; Schneider, Sabine; Streeck, Hendrik; Müller, Markus; Keppler, Oliver T. und Carell, Thomas (2022): Suppression of SARS-CoV-2 Replication with Stabilized and Click-Chemistry Modified siRNAs. In: Angewandte Chemie International Edition, Bd. 61, Nr. 38

Abstract

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-I-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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1433-7851
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 369799452