Oligonucleotides with Modifications of the Nucleotide-Linkage

An important aspect in the synthesis of oligonucleotides in gram or even kilogram quantities is the limited availability of 2-deoxynucleosides. The main source of their supply is salmon milt (the sperm sac of the male). An estimated annual crop of 237 000 tons of salmon corresponds to 15 tons of ODNs in case of application of standard methods of isolation and synthesis. It is evident that increased introduction of oligonucleotide drugs into the market will prompt search for other sources and development work on synthesis of nucleosides [55]. 

The half-life of ODNs in fetal calf serum is as short as 5 min [58], Therefore, it is evident that unmodified ODNs cannot be expected to be directly applicable in antisense drug therapy. Nucleases, which cleave the phosphoric ester bond, are the most relevant ODN-degrading 

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For RNA, artificial self-cleaving hammerhead ribozymes with a triazole linkage at the active site are reported [26]. Interestingly, triazole backbone modifications in RNA by CuAAC and SPAAC chemical hgation of 3 -azide and 5 -cyclooctyne oligonucleotides can further be reverse transcribed into DNA while one nucleotide is omitted at the linkage [95]. 

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