The use of oligonucleotides as selective inhibitors of gene expression offers a rational approach for the prevention and treatment of gene-mediated disorders. In the antisense approach, oligonucleotides complementary to specific sequences target mRNA or pre-mRNA involved in the development of the pathology. The therapeutic application of the antisense approach is currently under investigation in many different fields including oncology, hematopathogy and immunopathology (1-3). Nuclease degradation is one of the major limitation for the use of phosphodiester oligonucleotides as therapeutic agents since for example, their estimated half-life in 10% adult human serum is about 30 min (4, 5). Phosphorothioate oligonucleotides exhibit a chemical modification which dramatically reduces their sensitivity to nuclease degradation while preserving their activity as antisense agents.

Figure 1:

Phosphorothioate oligonucleotides do not kinase efficiently with P32 (5 to 10% incorporation).

Hybrids that phosphorothioate oligonucleotides form with complementary RNA or DNA sequences are less stable than those formed by phosphodiester oligonucleotides. Tm values decrease between 0.5℃ and 1℃ per phosphorothioate linkage.

Usually, antisense applications require large quantities of oligonucleotides. As phosphodiester oligonucleotides, phosphorothioates can be easily synthesized up to grams level, for preclinical and clinical applications.