Abstract
AbstractAntisense oligonucleotides (ASOs) have been developed as potential therapeutic agents for genetic disorders and various life‐threatening conditions. This class of therapeutics facilitates the treatment of the currently undruggable targets. However, their low stability and poor activity must be overcome by developing new analogs with improved functions. Therefore, in this study, we synthesized 4′‐C‐(S)‐ and 4′‐C‐(R)‐2‐aminopropoxy−thymidine and investigated the stability of the modified oligonucleotides containing these analogs. Interestingly, both analogs responded differently to thermal denaturation, with the former exhibiting good stability closer to that of the unmodified oligonucleotide and the latter exhibiting slight thermal destabilization. Notably, DNA/RNA heteroduplexes modified with these analogs elicited RNase H activity by degrading the heteroduplexes upon treatment. In addition, the serum stability of the modified oligodeoxynucleotides was significantly enhanced by the introduction of these analogs. Overall, our findings highlight the potential application of these analogs as ASO therapeutic candidates.
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