αβ Chimeric Antisense Oligonucleotides: Synthesis and Nuclease Resistance in Biological Media

A new type of chimeric oligonucleotides composed of α- and β-sections is described. The sequence of eight β-nucleotides flanked at 3′- or/and 5′-ends by nuclease-resistant α-oligonucleotides has been chosen as an effector domain to form a substrate for RNase H. The synthesized oligonucleotides are complementary to the translation initiation site of the pim protooncogene mRNA. We used the chemical ligation method to prepare the chimeric oligonucleotides. The thermal stability of heteroduplexes formed by the αβ oligonucleotides with a complementary strand is not significantly altered compared to that of their β-analogs. These oligonucleotides promote efficient RNase H-mediated cleavage of pim mRNA. Among the αβ oligonucleotides studied, one with an α-fragment bound by its 3′-end to the 3′-end of the β-octanucleotide proved to be the most resistant to nucleolytic digestion in human plasma, calf serum, and murine fibroblast lysate. This αβ oligonucleotide directs more specific RNA cleavage by RNase H than its ββ counterpart.