Artificial cationic oligosaccharides for heteroduplex oligonucleotide-type drugs

Heteroduplex oligonucleotides (HDOs), composed of a DNA/LNA gapmer and its complementary RNA, are a novel, promising candidates for antisense drugs. We previously reported oligodiaminogalactoses (ODAGals), designed to bind to A-type nucleic acid duplexes such as DNA/RNA and RNA/RNA duplexes. In this paper, we report oligodiguanidinogalactoses (ODGGals) as novel A-type duplex binding molecules. We aimed to study in detail applicability of ODAGals and ODGGals for additives to HDOs as an antisense drug. The effect of ODAGal4 (ODAGal 4mer) and ODGGal3 (ODGGal 3mer) on an HDO were evaluated by UV melting analyses, RNA degradation study by ribonuclease A (RNase A), and ribonuclease H (RNase H). Cleavage of a 13mer HDO by RNase A, which is considered to be the main cause of RNA degradation in serum, was effectively inhibited by the addition of only one equivalent of ODAGal4 and ODGGal3. In contrast, RNase H activity, which involves the cleavage of target RNAs by an antisense mechanism, was only slightly affected by the presence of the cationic oligosaccharides. These results suggest that ODAGal4 and ODGGal3 are useful because they could both stabilize the HDO and maintain RNase H activity of the gapmer.