Bridged Nucleic Acids Reloaded

Abstract

Oligonucleotides are key compounds widely used for research, diagnostics, and therapeutics. The rapid increase in oligonucleotide-based applications, together with the progress in nucleic acids research, led to the design of nucleotide analogs that when being part of these oligomers enhance their efficiency, bioavailability, or stability. One of the most useful nucleotide analogs are the first-generation bridge nucleic acids (BNA), also known as locked nucleic acids (LNA), which were used in combination with ribonucleotides, deoxyribonucleotides, or other analogs to construct oligomers with diverse applications. However, there is still room to improve their efficiency, bioavailability, stability, and, importantly, toxicity. A second generation BNA, BNANC (2'-O,4'-aminoethylene bridged nucleic acid), has been recently made available. Oligomers containing these analogs not only showed less toxicity when compared to LNA-containing compounds but in some cases also exhibited higher specificity. Although there are still few applications where BNANC-containing compounds were researched, the results are very promising warranting more efforts in incorporating these analogs for other applications. Furthermore, newer BNA compounds will be introduced in the near future offering great hope to oligonucleotide-based fields of research and applications.

Chemistry of Peptide-Oligonucleotide Conjugates: A Review

“…Therefore, the first-generation ASOs may be said to incorporate the modified phosphate linkages, such as phosphorothioate ( 1b ) [ 81 ], methyl phosphonate ( 1c ) [ 82 ], more rarely phosphorodithioate ( 1d ) [ 83 ] and boranophosphate ( 1e ) [ 84 ], and recently reported mesyl phosphoramidate ( 1g ) [ 85 , 86 ], as well as many others [ 87 , 88 ]. Another group of ASOs consists of oligonucleotides with modifications in the ribose ring that not only offer a varying degree of protection against nucleases but, even more importantly, increase the stability of the ASO-RNA duplex [ 89 , 90 , 91 ], notably 2′- O -methyl ( 2b ) [ 92 , 93 , 94 ], 2′- O -(2-methoxy)ethyl (MOE) ( 2c ) [ 95 , 96 ], 2′-deoxy-2′-α-fluoro ( 4 ) [ 97 ], and, especially, constrained ribose analogues such as bridged/locked nucleic acids (B/LNAs) ( 3 ) [ 98 , 99 , 100 , 101 ] and tricyclo-DNAs ( 5 ) [ 102 ]. A separate class of ASOs encompasses oligonucleotide analogs, in which the natural ribose-phosphate backbone is replaced by a suitable surrogate; typical examples would be peptide nucleic acids (PNAs) ( 6 ) [ 103 ] and phosphordiamidate morpholino oligomers (PMOs) ( 7 ) [ 104 , 105 ].…”

Silencing Antibiotic Resistance with Antisense Oligonucleotides

“… Chemical structures of nucleotide analogs mentioned in the text. The structures shown in this figure were published in the recent article by Soler Bistué et al [ 53 ]. …”