Amphiphilic Oligonucleotide Derivatives-Promising Tools for Therapeutics

Abstract

Recent advances in genetics and nucleic acid chemistry have created fundamentally new tools, both for practical applications in therapy and diagnostics and for fundamental genome editing tasks. Nucleic acid-based therapeutic agents offer a distinct advantage of selectively targeting the underlying cause of the disease. Nevertheless, despite the success achieved thus far, there remain unresolved issues regarding the improvement of the pharmacokinetic properties of therapeutic nucleic acids while preserving their biological activity. In order to address these challenges, there is a growing focus on the study of safe and effective delivery methods utilising modified nucleic acid analogues and their lipid bioconjugates. The present review article provides an overview of the current state of the art in the use of chemically modified nucleic acid derivatives for therapeutic applications, with a particular focus on oligonucleotides conjugated to lipid moieties. A systematic analysis has been conducted to investigate the ability of amphiphilic oligonucleotides to self-assemble into micelle-like structures, as well as the influence of non-covalent interactions of such derivatives with serum albumin on their biodistribution and therapeutic effects.

Keywords: amphiphilic oligonucleotides; modified nucleic acids; nucleic acid self-assembly; protein–oligonucleotide complexes; serum albumin.

Figure 1

Main therapeutic oligonucleotide (tON) mechanisms of action: (a)—RNase H-dependent mechanism of mRNA degradation; (b)—regulation of mRNA maturation process (regulation of splicing, inhibition of capping, inhibition of polyadenylation); (c)—blocking the landing site of the ribosome, resulting in the inhibition of translation; (d)—RNA interference; (e)—altering protein conformation and functions.

Figure 2

Biological barriers that influence the pharmacokinetic characteristics of oligonucleotide-based drugs: (a)—nuclease degradation; (b)—reticuloendothelial system; (c)—blocking the lateral movement of oligonucleotide from the vessel lumen into the interstitial fluid; (d)—low efficiency of cell penetration; (e)—endo-lysosomal entrapment; (f)—blood–brain barrier.

Figure 3

The structure of RNA nucleotide and potential sites for its chemical modification: (a)—modifications of inter-nucleotide phosphate; (b,c)—modifications of sugar backbone; (d)—modifications of nitrogenous bases; (e)—alternative chemistry (NB—nitrogenous base).

Figure 4

New classes of phosphate-modified oligonucleotides: (a)—phosphoryl guanidine derivatives; (b)—sulfonyl phosphoramidate derivatives; (c)—triazinyl phosphoramidate derivatives.

Figure 5

Chemical structure of morpholino oligonucleotides: (a)—6-membered morpholine rings, (b)—non-ionic phosphorodiamidate bond (NB—nitrogenous base).

Figure 6

N-acetylgalactosamine (GalNAc) fragment conjugated to siRNA.

Figure 7

Structural formula of a lipid moiety containing two C18 alkyl groups, which are covalently linked to the 5′-end of the ON (ON—oligonucleotide sequences containing five to fifty nucleotide units).

Figure 8

An ON–lipid conjugate comprising two 18-carbon alkyl groups, which are covalently linked to the 5′-end of the ON (ON—oligonucleotide sequence).

Figure 9

The chemical structure of the modified nucleotide linkage employed in [109,128] (B—nitrogenous base).

Figure 10

The chemical structures of the siRNA conjugates in [131].

Figure 11

The chemical structure of the 3′-terminal link has been modified at the 3′-position by (S)-(+)-ibuprofen (ASO—antisense oligonucleotide).

Figure 12

The structure of the cholesterol fragment conjugated to PS ASO (ASO—antisense oligonucleotide).

Figure 13

The structures of the fragments conjugated to PS ASO (ASO—antisense oligonucleotide).

Figure 14

The chemical structure of the N₂′-functionalised amino-LNA monomer (R—myristic acid or palmitic acid residue; B—nitrogenous base; X—O or S atom).

Figure 15

The chemical structure of the 5′-terminal link (ASO—antisense oligonucleotide; R—fatty acid residue).

Figure 16

siRNA conjugated to stearic acid (siRNA—small interfering RNA; R—residue C₁₇H₃₅).

Figure 17

The chemical structure of the 5′-terminal nucleotide linkage (ASO—antisense oligonucleotide).

Figure 18

The chemical structure of a non-nucleotide dodecyl-containing link within an oligonucleotide.

Figure 19

The chemical structure of triazinyl phosphoramidate modification functionalized with two dodecyl groups.

Figure 20

The chemical structure of the phosphoramidite used to insert the F base into the aptamer sequence (DMTr—dimethoxytriphenylmethyl).