This conformational preorganization often results in increased thermal stability and, as a consequence of the structural changes, to improved nuclease resistance. Many nucleic acid modifications are designed to modulate the conformation of the sugar-phosphate backbone, preorganizing them for duplex formation. Therefore, great effort has been made to develop chemically modified oligonucleotides that are able to form Watson-Crick duplexes with increased thermal stability. The key requirements for potential therapeutic oligonucleotides are resistance against nuclease degradation and high affinity to complementary nucleic acids.
Modified nucleic acids have shown widespread utility as diagnostic tools and oligonucleotide-based drugs.
The conformation of the tc-DNA strand in the three determined structures is nearly identical and despite the different nature and local geometry of the complementary strand, the overall structures of the examined duplexes are very similar suggesting that the tc-DNA strand dominates the duplex structure. All sugars of the tc-DNA and RNA residues adopt a North conformation whereas the DNA deoxyribose are found in a South-East-North conformation equilibrium. All three investigated duplexes maintain a right-handed helical structure with Watson-Crick base pairing and overall geometry intermediate between A- and B-type, but closer to A-type structures. Here, we report the structures of a fully modified tc-DNA oligonucleotide paired with either complementary RNA, DNA or tc-DNA. To date, no high-resolution structural data is available for fully modified tc-DNA duplexes and little is known about the origins of their enhanced thermal stability. Remarkably, recent studies revealed that tc-DNA antisense oligonucleotides (AO) hold great promise for the treatment of Duchenne muscular dystrophy and spinal muscular atrophy. Tc-DNA is a conformationally constrained oligonucleotide analogue which shows significant increase in thermal stability when hybridized with RNA, DNA or tc-DNA.
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