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Multifaceted World of Chemically Modified Oligonucleotides for Nucleic Acid Therapeutics

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 454

Special Issue Editor

1. Head of Lab, Laboratory of Bionanotechnology, Department of Physics, Novosibirsk State University, Novosibirsk 630090, Russia
2. Laboratory of Nucleic Acid Chemistry, Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk 630090, Russia
Interests: nucleic acid chemistry; design of DNA and RNA analogues; oligonucleotide synthesis; modification and conjugation; oligonucleotide therapeutics; nucleic acid drug delivery; DNA nanotechnology

Special Issue Information

Dear Colleagues,

The year 2023 marks the twin anniversary of nucleic acid therapeutics, i.e., 45 years since the publication (1978) of the celebrated paper written by Paul Zamecnik and Mary Stephenson, which heralded the advent of antisense technology, and 25 years since the approval of the first oligonucleotide drug, Vitravene (fomivirsen), in 1998. However, as 2023 nears the end, I believe another paper ought to be recalled: an early work by Nina Grineva et al. that appeared 55 years ago (Belikova et al., 1967, PMID 6073336). For the first time, it put forward the idea of exploiting the sequence-selective Watson–Crick duplex formation between an oligonucleotide and its complementary nucleic acid target (DNA in the paper) to achieve a therapeutic effect. Oligonucleotide synthesis was still in its infancy at that moment, although the same year (1967), Fritz Eckstein described the synthesis of the first ever enzymatically resistant phosphate mimic, replacing one of the nonbridging oxygen atoms of the phosphodiester group with sulfur—a dinucleoside phosphorothioate that, decades later, gave rise to first-generation antisense oligonucleotides such as fomivirsen. Consequently, it took over ten years for the Grineva concept to be experimentally verified in Zamecnik’s study, which firmly identified the biological target of antisense oligonucleotides to be an RNA molecule (mRNA in that case). At long last, chemically modified oligonucleotides received nearly universal recognition as precision tools for antisense- and RNAi-based gene therapies and more (e.g., mRNA vaccines, CRISPR/Cas, etc.). Every year since 2016 up until now, one, two or even three of these drugs would enter the pharmaceutical market, the latest being the siRNA Amvuttra (vutrisiran) in June 2022, and the morpholino antisense Amondys 45 (casimersen) in February 2021.

The aim of this Special Issue is to provide a snapshot of contemporary modified oligonucleotides, as well as their design, synthesis and applications as potential therapeutics. Suitable topics include, but are not limited to, oligonucleotides (including gapmers) with various phosphate/sugar/nucleobase modifications and terminal pendant groups, 2′-O-alkyl RNAs, bridged/locked nucleic acids (B/LNAs), peptide nucleic acids (PNAs), phosphorodiamidate morpholino oligonucleotides (PMOs), etc., cell/tissue-deliverable peptides, lipid and polymer/dendrimer conjugates, oligonucleotide-functionalized nanoparticles (spherical nucleic acids (SNAs), etc.), DNAzymes, DNA/RNA aptamers, CpG oligonucleotides, and therapeutic applications thereof, including genetic disorders/splice switching, neurodegenerative, cardiovascular and metabolic diseases, anticancer, antiviral, antibacterial, immunomodulatory, etc.

Dr. Dmitry A. Stetsenko
Guest Editor

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Keywords

  • DNA and RNA analogues
  • phosphate mimics
  • sugar-modified oligonucleotides
  • base modifications
  • nucleic acid therapeutics

Published Papers (1 paper)

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Research

15 pages, 2443 KiB  
Communication
A Convenient Oligonucleotide Conjugation via Tandem Staudinger Reaction and Amide Bond Formation at the Internucleotidic Phosphate Position
Int. J. Mol. Sci. 2024, 25(4), 2007; https://doi.org/10.3390/ijms25042007 - 07 Feb 2024
Viewed by 337
Abstract
Staudinger reaction on the solid phase between an electronodeficit organic azide, such as sulfonyl azide, and the phosphite triester formed upon phosphoramidite coupling is a convenient method for the chemical modification of oligonucleotides at the internucleotidic phosphate position. In this work, 4-carboxybenzenesulfonyl azide, [...] Read more.
Staudinger reaction on the solid phase between an electronodeficit organic azide, such as sulfonyl azide, and the phosphite triester formed upon phosphoramidite coupling is a convenient method for the chemical modification of oligonucleotides at the internucleotidic phosphate position. In this work, 4-carboxybenzenesulfonyl azide, either with a free carboxy group or in the form of an activated ester such as pentafluorophenyl, 4-nitrophenyl, or pentafluorobenzyl, was used to introduce a carboxylic acid function to the terminal or internal internucleotidic phosphate of an oligonucleotide via the Staudinger reaction. A subsequent treatment with excess primary alkyl amine followed by the usual work-up, after prior activation with a suitable peptide coupling agent such as a uronium salt/1-hydroxybenzotriazole in the case of a free carboxyl, afforded amide-linked oligonucleotide conjugates in good yields including multiple conjugations of up to the exhaustive modification at each phosphate position for a weakly activated pentafluorobenzyl ester, whereas more strongly activated and, thus, more reactive aryl esters provided only single conjugations at the 5′-end. The conjugates synthesized include those with di- and polyamines that introduce a positively charged side chain to potentially assist the intracellular delivery of the oligonucleotide. Full article
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