Backbone Modification of Nucleic Acids: Synthesis, Structure and Therapeutic Applications

Abstract

Nucleic acids have been extensively modified by replacing the phosphodiester group or the whole sugar phosphodiester with alternative anionic, neutral and cationic structures. Several of these modified oligonucleotides exhibit improved properties including enhanced recognition and binding to RNA, duplex DNA and proteins. This has resulted in the development of new and more potent antisense and antigene agents, as well as aptamers. Furthermore, backbone modified oligonucleotides have also been used in the development of several alternative strategies, which rely on altogether different mechanisms of action and show significant promise for therapeutic intervention. In this review the latest advances in the synthesis and evaluation of the most promising backbone modified oligos will be discussed, with a view to their future as novel pharmaceuticals.

Chemical Modification of Oligonucleotides for Therapeutic, Bioanalytical and other Applications

“…Many moieties that are not chemically similar to phosphodiester, such as amide, guanidine and acetal have been used to replace the phosphodiester linkage. [1] More recently Strçmberg et al explored the combination of formacetal linkages and 2'-OMe modifications in oligoribonucleotides (5). The formacetal modification on its own has a stabilising effect on RNA duplexes of 0 to +0.9 8C DT m /mod at physiological salt concentrations, but a destabilising effect (DT m /mod À0.4 to À0.8 8C) at high salt concentrations.…”

“…[1] Whilst the antisense field suffered to some extent from unrealistically high expectations for clinical applications, in some quarters, efforts to develop modified oligonucleotides and nucleic acid mimic has continued at a pace. Further impetus for the field came with the discovery of RNA interference, which has reinvigorated research into chemical modification of oligonucleotides to stabilise and improve the efficacy of siRNAs.…”

“…This review also highlights how well-known limitations, such as stability, transfection, targeting etc., are being overcome. To a large extent the review covers the most recent literature and the reader is referred to our previous review of this field [1] for details of earlier work in this area.…”

Diastereomerically pure nucleoside‐5′‐O‐(2‐thio‐4,4‐pentamethylene‐1,3,2‐oxathiaphospholane)s—Substrates for synthesis of P‐chiral derivatives of nucleoside‐5′‐O‐phosphorothioates

“…For that purpose, numerous analogs carrying modifications within nucleobases, ribose, deoxyribose, and phosphate moieties have been obtained. 7,8 Among these, the phosphorothioate nucleotides/oligonucleotides, in which one of the nonbridging phosphate oxygen atoms was substituted with a sulfur atom, were most extensively studied, both in in vitro and in vivo experiments. 9,10 Also, it should be noted that only recently phosphorothioation of DNA in bacteria has been discovered.…”

Synthesis of Formacetal‐Linked Dinucleotides to Facilitate dsDNA Bending and Binding to the Homeodomain of Pax6

“…Within a large variety of oligonucleotide backbone modifications [18] the replacement of the negatively charged phosphodiester group by the achiral and neutral formacetal linker results in a double helix that retains a topology similar to B-DNA. The double strand stability is reduced by about 3°C per modification, and the formacetal backbone has only a slight influence on the backbone conformation.…”