Abstract
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.
Highlights
Antisense oligonucleotides (ASOs) are among the most successful nucleic acid candidates
One of the designs of effective ribonuclease H (RNase H)-dependent ASOs is gapmer ASOs, which contain a central window of consecutive DNA and a wing region consisting of RNA-like nucleotides with high affinity for complementary RNA, such as 2′-OMe RNA and LNA6
We reported the synthesis of β-(1 → 4)-linked 2,6-diamino-2, 6-dideoxy D-galactopyranose oligomers (ODAGals, oligodiaminogalactoses), and showed that the ODAGal 4mer (ODAGal4) could effectively bind to an siRNA and protect it almost completely against cleavage by RNase A11
Summary
Antisense oligonucleotides (ASOs) are among the most successful nucleic acid candidates. The second type is steric blocker ASOs, which mask the function of the target RNA by duplex formation In the former mechanism, the ASOs must contain consecutive DNA region for recognition by RNase H, as well as highly chemically modified nucleic acids to ensure the biological stability of the ASOs and the thermodynamic stability of the ASO/RNA duplex. Since gapmer type oligonucleotides was reported to show RNase H activity in 1980s7,8, they have been eagerly studied as nucleic acid drug candidates[2,6,9] and the mipomersen is a successful one. We evaluated the binding properties of ODGGals to nucleic acid duplexes, and the effect of ODGGals and ODAGals on the RNase A resistance of an HDO and the RNase H activity of the gapmer
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