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

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 c...

Full description

Saved in:
Bibliographic Details
Published in:Angewandte Chemie International Edition 2022-09, Vol.61 (38), p.e202204556-n/a
Main Authors: Traube, Franziska R., Stern, Marcel, Tölke, Annika J., Rudelius, Martina, Mejías‐Pérez, Ernesto, Raddaoui, Nada, Kümmerer, Beate M., Douat, Céline, Streshnev, Filipp, Albanese, Manuel, Wratil, Paul R., Gärtner, Yasmin V., Nainytė, Milda, Giorgio, Grazia, Michalakis, Stylianos, Schneider, Sabine, Streeck, Hendrik, Müller, Markus, Keppler, Oliver T., Carell, Thomas
Format: Article
Language:English
Subjects:
ACE2
Angiotensin-converting enzyme 2
Antiviral activity
antiviral compounds
Apoptosis
Cell lines
Chemistry
Corona pandemic
Cytotoxicity
Ligands
Mutation
peptide RNA conjugates
Peptides
Receptors
Replication
SARS-CoV-2
Severe acute respiratory syndrome
Severe acute respiratory syndrome coronavirus 2
siRNA
Toxicity
Viral diseases
Viruses
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 CuI‐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. siRNAs protect cells from SARS‐CoV‐2 and can be quickly adjusted to variants of concern. An alkyne moiety was integrated at the 3′ end of the siRNA to enable chemical modification of the siRNA via CuI‐catalysed click‐chemistry. Following this strategy, the siRNA can be conjugated to receptor ligands such as hACE2‐binding peptides, which allows target‐specific delivery.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202204556