Application of 4′-C-α-aminoethoxy-2′-O-methyl-5-propynyl-uridine for antisense therapeutics

Abstract

Owing to the increased public interest and advances in chemical modifications, the approval of antisense therapeutics, a class of mRNA-targeting DNA-based oligonucleotide therapeutics, has accelerated in recent years. It was previously reported that siRNAs with several 4′-C-α-aminoethoxy-2′-O-methyl-uridine (4AEoU) analogs could maintain moderate thermal stability similar to the native ones while showing robust nuclease stability. In this study, we further expanded the application of 4AEo modification to antisense therapeutics and achieved superior thermal stability by adding the uracil 5-propynyl modification. Antisense oligonucleotides containing 4′-C-α-aminoethoxy-2′-O-methyl-5-propynyl-uridine (4AEo^pU) could efficiently activate RNase H-mediated antisense in vitro in the presence of native DNA gaps. These results encourage future studies of 4AEo^pU-containing antisense therapeutics.