ArticleNucleic acids research2017
Amide linkages mimic phosphates in RNA interactions with proteins and are well tolerated in the guide strand of short interfering RNAs.
Article in Nucleic acids research, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 45 citations in OpenAlex.
- Structural insights into RNase H catalytic mechanism from room-temperature X-ray and neutron crystallography of apo- and RNA/DNA hybrid-bound enzyme.Current research in structural biology · 2026Article
- From liquid-phase synthesis to chemical ligation: preparation of oligonucleotides and their backbone analogs in solution.Nucleic acids research · 2025Review
- siRNA Features-Automated Machine Learning of 3D Molecular Fingerprints and Structures for Therapeutic Off-Target Data.International journal of molecular sciences · 2025Article
- Amide Internucleoside Linkages Suppress the MicroRNA-like Off-Target Activity of Short Interfering RNA.ACS chemical biology · 2025Article
- Synthesis, Biophysical and Biological Evaluation of Splice-Switching Oligonucleotides with Multiple LNA-Phosphothiotriester Backbones.Journal of the American Chemical Society · 2024Article
- Synthesis and Properties of RNA Modified with Thioamide Internucleoside Linkage.Chembiochem : a European journal of chemical biology · 2024Article
- Synthesis and Properties of RNA Modified with Cationic Amine Internucleoside Linkage.ACS chemical biology · 2024Article
- Drug Discovery Perspectives of Antisense Oligonucleotides.Biomolecules & therapeutics · 2023Review
- Chemistry, structure and function of approved oligonucleotide therapeutics.Nucleic acids research · 2023Review
- Amide Modifications in the Seed Region of the Guide Strand Improve the On-Target Specificity of Short Interfering RNA.ACS chemical biology · 2023Article
- Chemical Modifications of CRISPR RNAs to Improve Gene-Editing Activity and Specificity.Journal of the American Chemical Society · 2022Review
- An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides.Nature communications · 2022Article
- Optimization of Automated Synthesis of Amide-Linked RNA.ACS omega · 2022Article
- Amide Internucleoside Linkages Are Well Tolerated in Protospacer Adjacent Motif-Distal Region of CRISPR RNAs.ACS chemical biology · 2022Article
- siRNAs containing 2'-fluorinated Northern-methanocarbacyclic (2'-F-NMC) nucleotides: in vitro and in vivo RNAi activity and inability of mitochondrial polymerases to incorporate 2'-F-NMC NTPs.Nucleic acids research · 2021Article
- Chemical strategies for strand selection in short-interfering RNAs.RSC advances · 2021Review
- Beyond ribose and phosphate: Selected nucleic acid modifications for structure-function investigations and therapeutic applications.Beilstein journal of organic chemistry · 2021Review
- Amide-Modified RNA: Using Protein Backbone to Modulate Function of Short Interfering RNAs.Accounts of chemical research · 2020Article
- Synthesis and Evaluation of Neutral Phosphate Triester Backbone-Modified siRNAs.ACS medicinal chemistry letters · 2020Article
- Synthesis and Biological Activity of Short Interfering RNAs Having Several Consecutive Amide Internucleoside Linkages.Chemistry (Weinheim an der Bergstrasse, Germany) · 2020Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
While the use of RNA interference (RNAi) in molecular biology and functional genomics is a well-established technology, in vivo applications of synthetic short interfering RNAs (siRNAs) require chemical modifications. We recently found that amides as non-ionic replacements for phosphodiesters may be useful modifications for optimization of siRNAs. Herein, we report a comprehensive study of systematic replacement of a single phosphate with an amide linkage throughout the guide strand of siRNAs. The results show that amides are surprisingly well tolerated in the seed and central regions of the guide strand and increase the silencing activity when placed between nucleosides 10 and 12, at the catalytic site of Argonaute. A potential explanation is provided by the first crystal structure of an amide-modified RNA-DNA with Bacillus halodurans RNase H1. The structure reveals how small changes in both RNA and protein conformation allow the amide to establish hydrogen bonding interactions with the protein. Molecular dynamics simulations suggest that these alternative binding modes may compensate for interactions lost due to the absence of a phosphodiester moiety. Our results suggest that an amide can mimic important hydrogen bonding interactions with proteins required for RNAi activity and may be a promising modification for optimization of biological properties of siRNAs.
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Registered trials
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