Amidation of Phosphonoacetate-Modified Oligonucleotides and Evaluation of the Properties of the Synthesized Oligonucleotides

Chemical modification of the phosphate backbone in the discovery of oligonucleotide therapeutics has recently attracted attention. However, most phosphate-backbone modifications require the synthesis of phosphoramidite building blocks, which limits rapid structural diversification and systematic structure-activity relationship studies. In this study, amidation of phosphonoacetate (PACE)-modified oligonucleotides was developed. Our modification method enables the rapid introduction of diverse substituents to the phosphate backbone of oligonucleotides, avoidance of novel phosphoramidite synthesis, and systematic functional evaluation of phosphate-backbone-modified oligonucleotides.