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The Medicinal Chemistry of Artificial Nucleic Acids and Therapeutic Oligonucleotides - PubMed

  • ️Sat Jan 01 2022

Review

The Medicinal Chemistry of Artificial Nucleic Acids and Therapeutic Oligonucleotides

Miklós Bege et al. Pharmaceuticals (Basel). 2022.

Abstract

Nucleic acids play a central role in human biology, making them suitable and attractive tools for therapeutic applications. While conventional drugs generally target proteins and induce transient therapeutic effects, nucleic acid medicines can achieve long-lasting or curative effects by targeting the genetic bases of diseases. However, native oligonucleotides are characterized by low in vivo stability due to nuclease sensitivity and unfavourable physicochemical properties due to their polyanionic nature, which are obstacles to their therapeutic use. A myriad of synthetic oligonucleotides have been prepared in the last few decades and it has been shown that proper chemical modifications to either the nucleobase, the ribofuranose unit or the phosphate backbone can protect the nucleic acids from degradation, enable efficient cellular uptake and target localization ensuring the efficiency of the oligonucleotide-based therapy. In this review, we present a summary of structure and properties of artificial nucleic acids containing nucleobase, sugar or backbone modifications, and provide an overview of the structure and mechanism of action of approved oligonucleotide drugs including gene silencing agents, aptamers and mRNA vaccines.

Keywords: RNA interference; antisense; aptamer; gene silencing; mRNA vaccine; oligonucleotides; phosphorodiamidate morpholino oligomers (PMOs); phosphorothioate; splicing modulation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1

The structure of RNA and DNA and Watson–Crick and Hoogsteen base pair systems.

Figure 2
Figure 2

Sugar puckering in nucleic acids.

Scheme 1
Scheme 1

Solid-phase synthesis of oligonucleotides by phosphoramidite chemistry. The iterative steps of synthetic cycle are highlighted in red. DMTr: 4,4′-dimethoxytrityl, TBDMS: t-butyldimethylsilyl, TCA: trichloroacetic acid, Ac2O: acetic anhydride, CPG: controlled pore glass.

Figure 3
Figure 3

Modified bases in XNAs.

Figure 4
Figure 4

The structure of DNA and XNAs with other sugars than β-D-ribofuranose.

Figure 5
Figure 5

Structure of CNAs, CeNA, HNAs and PMO. PMOs contain both sugar and backbone modifications.

Figure 6
Figure 6

Bi- and tricyclic XNAs.

Figure 7
Figure 7

Acyclic NA analogues.

Figure 8
Figure 8

2′-Substituted nucleic acid analogues.

Figure 9
Figure 9

XNAs with negatively charged backbone.

Figure 10
Figure 10

XNAs with neutral backbone.

Figure 11
Figure 11

XNAs with peptide type backbones.

Figure 12
Figure 12

XNAs with positively charged backbone.

Figure 13
Figure 13

Structure of pegaptanib.

Figure 14
Figure 14

Structure of mipomersen.

Figure 15
Figure 15

Mechanism of action of eteplirsen.

Figure 16
Figure 16

Mechanism of action of nusinersen in patient with SMA. SMA: spinal muscular atrophy, SMN2: survival motor neuron protein gene 2.

Figure 17
Figure 17

Structure of patisiran.

Figure 18
Figure 18

Structure of inotersen.

Figure 19
Figure 19

Structure of volanesorsen.

Figure 20
Figure 20

Structure of the GalNAc-siRNA conjugate givosiran.

Figure 21
Figure 21

Structure of viltolarsen.

Figure 22
Figure 22

Structure of N1-methylpseudouridine (A) and the 5′-cap of tozinameran (B).

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