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A Versatile Solid-Phase Approach to the Synthesis of Oligonucleotide Conjugates with Biodegradable Hydrazone Linker.

Authors :
Meschaninova MI
Entelis NS
Chernolovskaya EL
Venyaminova AG
Source :
Molecules (Basel, Switzerland) [Molecules] 2021 Apr 07; Vol. 26 (8). Date of Electronic Publication: 2021 Apr 07.
Publication Year :
2021

Abstract

One of the ways to efficiently deliver various drugs, including therapeutic nucleic acids, into the cells is conjugating them with different transport ligands via labile or stable bonds. A convenient solid-phase approach for the synthesis of 5'-conjugates of oligonucleotides with biodegradable pH-sensitive hydrazone covalent bonds is proposed in this article. The approach relies on introducing a hydrazide of the ligand under aqueous/organic media to a fully protected support-bound oligonucleotide containing aldehyde function at the 5'-end. We demonstrated the proof-of-principle of this approach by synthesizing 5'-lipophilic (e.g., cholesterol and α-tocopherol) conjugates of modified siRNA and non-coding RNAs imported into mitochondria (antireplicative RNAs and guide RNAs for Mito-CRISPR/system). The developed method has the potential to be extended for the synthesis of pH-sensitive conjugates of oligonucleotides of different types (ribo-, deoxyribo-, 2'- O -methylribo-, and others) with ligands of different nature.

Details

Language :
English
ISSN :
1420-3049
Volume :
26
Issue :
8
Database :
MEDLINE
Journal :
Molecules (Basel, Switzerland)
Publication Type :
Academic Journal
Accession number :
33917095
Full Text :
https://doi.org/10.3390/molecules26082119